4878 lines
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Entry
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- *164840 - MYCN PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYCN
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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">*164840</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/164840">Table View</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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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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<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=ENSG00000134323;t=ENST00000281043" 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=4613" 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=164840" 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 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="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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</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=ENSG00000134323;t=ENST00000281043" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001293228,NM_001293231,NM_001293233,NM_005378,XM_047444434" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005378" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=164840" 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 id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01278&isoform_id=01278_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/MYCN" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/35075,35076,35079,127604,188962,386982,386983,871358,4467844,5042221,11692796,12803749,13661735,19923312,30583607,62822404,119621290,119621291,119621292,119621293,194388872,194389958,269949614,484259493,648216288,648216291,648216293,1022612243,2217328164,2462573475" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P04198" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div 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=4613" 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=ENSG00000134323;t=ENST00000281043" 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=MYCN" 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=MYCN" 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+4613" 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/MYCN" 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:4613" 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/4613" 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=chr2&hgg_gene=ENST00000281043.4&hgg_start=15940550&hgg_end=15947004&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 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:7559" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/mycn" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=164840[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=164840[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MYCN/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000134323" 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=MYCN" 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=MYCN" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=MYCN" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MYCN&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/PA31359" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:7559" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/search?q=MGI:1332242 MGI:97357" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/MYCN#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/batch/summary?idType=MGI&ids=MGI:1332242 MGI:97357" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/4613/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=4613" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-020711-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4613" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=MYCN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 702431004<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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164840
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
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<span class="mim-font">
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MYCN PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYCN
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
V-MYC AVIAN MYELOCYTOMATOSIS VIRAL-RELATED ONCOGENE, NEUROBLASTOMA-DERIVED<br />
|
|
ONCOGENE NMYC<br />
|
|
NMYC ONCOGENE<br />
|
|
AVIAN MYELOCYTOMATOSIS VIRAL-RELATED ONCOGENE, NEUROBLASTOMA-DERIVED<br />
|
|
NEUROBLASTOMA MYC ONCOGENE
|
|
</span>
|
|
</h4>
|
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</div>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MYCN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MYCN</a></em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/61?start=-3&limit=10&highlight=61">2p24.3</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:15940550-15947004&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'})">2:15,940,550-15,947,004</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=164280,620748" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/61?start=-3&limit=10&highlight=61">
|
|
2p24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Feingold syndrome 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/164280"> 164280 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
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|
|
|
|
|
|
|
</tr>
|
|
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|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Megalencephaly-polydactyly syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620748"> 620748 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
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<p>The MYCN oncogene encodes a transcription factor belonging to the MYC (<a href="/entry/190080">190080</a>) family. It is primarily expressed in normal developing embryos and is thought to be critical in brain and other neural development. MYCN amplification is found in 20 to 30% of neuroblastoma tumors (see <a href="/entry/256700">256700</a>), the most frequent extracranial solid tumors of childhood (summary by <a href="#40" class="mim-tip-reference" title="Wei, J. S., Song, Y. K., Durinck, S., Chen, Q.-R., Cheuk, A. T. C., Tsang, P., Zhang, Q., Thiele, C. J., Slack, A., Shohet, J., Khan, J. <strong>The MYCN oncogene is a direct target of miR-34a.</strong> Oncogene 27: 5204-5213, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18504438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18504438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18504438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2008.154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18504438">Wei et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18504438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#16" class="mim-tip-reference" title="Kohl, N. E., Kanda, N., Schreck, R. R., Bruns, G., Latt, S. A., Gilbert, F., Alt, F. W. <strong>Transposition and amplification of oncogene-related sequences in human neuroblastomas.</strong> Cell 35: 359-367, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6197179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6197179</a>] [<a href="https://doi.org/10.1016/0092-8674(83)90169-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6197179">Kohl et al. (1983)</a> isolated a genomic DNA segment homologous to the classic MYC oncogene that was amplified in neuroblastoma cell lines. They designated the gene corresponding to the DNA segment NMYC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6197179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Michitsch, R. W., Melera, P. W. <strong>Nucleotide sequence of the 3-prime exon of the human N-myc gene.</strong> Nucleic Acids Res. 13: 2545-2558, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2987858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2987858</a>] [<a href="https://doi.org/10.1093/nar/13.7.2545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2987858">Michitsch and Melera (1985)</a> cloned a partial NMYC cDNA from a neuroblastoma cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2987858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#37" class="mim-tip-reference" title="Stanton, L. W., Schwab, M., Bishop, J. M. <strong>Nucleotide sequence of the human N-myc gene.</strong> Proc. Nat. Acad. Sci. 83: 1772-1776, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2869488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2869488</a>] [<a href="https://doi.org/10.1073/pnas.83.6.1772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2869488">Stanton et al. (1986)</a> cloned a full-length NMYC cDNA. The deduced 456-amino acid protein has a calculated molecular mass of 49 kD. NMYC shares a high degree of similarity with MYC, particularly in the putative C-terminal DNA-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2869488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Ramsay, G., Stanton, L., Schwab, M., Bishop, J. M. <strong>Human proto-oncogene N-myc encodes nuclear proteins that bind DNA.</strong> Molec. Cell. Biol. 6: 4450-4457, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3796607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3796607</a>] [<a href="https://doi.org/10.1128/mcb.6.12.4450-4457.1986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3796607">Ramsay et al. (1986)</a> identified 2 proteins originating from the same NMYC mRNA. Both were phosphorylated and exceptionally unstable. They were located in the cell nucleus and were bound to both single- and double-stranded DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3796607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By sequencing several NMYC cDNA clones, <a href="#36" class="mim-tip-reference" title="Stanton, L. W., Bishop, J. M. <strong>Alternative processing of RNA transcribed from NMYC.</strong> Molec. Cell. Biol. 7: 4266-4272, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3437890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3437890</a>] [<a href="https://doi.org/10.1128/mcb.7.12.4266-4272.1987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3437890">Stanton and Bishop (1987)</a> determined that transcription from the NMYC gene is complex. Transcription initiates at 2 clusters of sites that appear to be under the control of 2 distinct promoters. In addition, 2 alternative first exons, 1a and 1b, are spliced to a common acceptor site in exon 2. Both mRNAs encode the 65- and 67-kD NMYC proteins. However, exons 1a and 1b both contain putative short open reading frames, 2 of which are in favorable Kozak contexts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3437890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in situ hybridization and S1 nuclease protection analysis of early second-trimester human fetal tissues, <a href="#11" class="mim-tip-reference" title="Grady, E. F., Schwab, M., Rosenau, W. <strong>Expression of N-myc and c-src during the development of fetal human brain.</strong> Cancer Res. 47: 2931-2936, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3552210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3552210</a>]" pmid="3552210">Grady et al. (1987)</a> found high NMYC RNA levels in cerebral germinal layer and primordial cortex and lower levels in the intermediate layer. After week 20, NMYC expression remained high in the undifferentiated outer cortex, but declined in the attenuated germinal layer and in the differentiating inner cortex. The primitive retina had high NMYC RNA levels in the inner nuclear and ganglion cell layers between 12 and 21 weeks. Lower levels of NMYC RNA were detected in some cells of lung and placenta. <a href="#11" class="mim-tip-reference" title="Grady, E. F., Schwab, M., Rosenau, W. <strong>Expression of N-myc and c-src during the development of fetal human brain.</strong> Cancer Res. 47: 2931-2936, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3552210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3552210</a>]" pmid="3552210">Grady et al. (1987)</a> concluded that NMYC RNA is elevated in immature neural cells and disappears with differentiation. They speculated that NMYC upregulation may be unrelated to mitosis, since high levels occur in the primordial cortex, which grows by accretion and not by cell division. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3552210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#37" class="mim-tip-reference" title="Stanton, L. W., Schwab, M., Bishop, J. M. <strong>Nucleotide sequence of the human N-myc gene.</strong> Proc. Nat. Acad. Sci. 83: 1772-1776, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2869488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2869488</a>] [<a href="https://doi.org/10.1073/pnas.83.6.1772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2869488">Stanton et al. (1986)</a> determined that the MYCN gene is GC rich and contains 3 exons. Exon 1 is noncoding and contributes to a long 5-prime leader sequence. The 5-prime UTR contains 2 potential TATA boxes, the first of which probably denotes the major promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2869488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Stanton, L. W., Bishop, J. M. <strong>Alternative processing of RNA transcribed from NMYC.</strong> Molec. Cell. Biol. 7: 4266-4272, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3437890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3437890</a>] [<a href="https://doi.org/10.1128/mcb.7.12.4266-4272.1987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3437890">Stanton and Bishop (1987)</a> identified alternative first exons, 1a and 1b, in the MYCN gene that are spliced to the common exons 2 and 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3437890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Krystal, G. W., Armstrong, B. C., Battey, J. F. <strong>N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts.</strong> Molec. Cell. Biol. 10: 4180-4191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695323</a>] [<a href="https://doi.org/10.1128/mcb.10.8.4180-4191.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695323">Krystal et al. (1990)</a> found that the GC-rich promoter of the MYCN gene functions as a bidirectional promoter to drive transcription of both the MYCN and NCYM genes in opposite directions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Kanda, N., Schreck, R., Alt, F., Bruns, G., Baltimore, D., Latt, S. <strong>Isolation of amplified DNA sequences from IMR-32 human neuroblastoma cells: facilitation by fluorescence-activated flow sorting of metaphase chromosomes.</strong> Proc. Nat. Acad. Sci. 80: 4069-4073, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6575396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6575396</a>] [<a href="https://doi.org/10.1073/pnas.80.13.4069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6575396">Kanda et al. (1983)</a> used human-mouse hybrid cells to map NMYC to chromosome 2. In situ hybridization indicated that NMYC is on chromosome 2p. <a href="#32" class="mim-tip-reference" title="Schwab, M., Varmus, H. E., Bishop, J. M., Grzeschik, K.-H., Naylor, S. L., Sakaguchi, A. Y., Brodeur, G., Trent, J. <strong>Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc.</strong> Nature 308: 288-291, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6700732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6700732</a>] [<a href="https://doi.org/10.1038/308288a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6700732">Schwab et al. (1984)</a> assigned NMYC to chromosome 2p23 or 2p24. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6700732+6575396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Garson, J. A., van den Berghe, J. A., Kemshead, J. T. <strong>Novel non-isotopic in situ hybridization technique detects small (1 kb) unique sequences in routinely G-banded human chromosomes: fine mapping of N-myc and beta-NGF genes.</strong> Nucleic Acids Res. 15: 4761-4770, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3299258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3299258</a>] [<a href="https://doi.org/10.1093/nar/15.12.4761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3299258">Garson et al. (1987)</a> used a novel in situ hybridization technique to map NMYC to chromosome 2p24. The nonradioactive technique combined the high spatial resolution and rapid signal development of the nonisotope approach with the previously unrivaled sensitivity of autoradiography. The method, which used biotin-labeled DNA probes and a streptavidin-alkaline phosphatase-based detection system, was compatible with G-banding and could be performed on archival material. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3299258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By study of mouse-hamster somatic cell hybrids, <a href="#5" class="mim-tip-reference" title="Campbell, G. R., Zimmerman, K., Blank, R. D., Alt, F. W., D'Eustachio, P. <strong>Chromosomal location of N-myc and L-myc genes in the mouse.</strong> Oncogene Res. 4: 47-54, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2654812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2654812</a>]" pmid="2654812">Campbell et al. (1989)</a> mapped the mouse equivalent of NMYC to chromosome 12. By study of RFLPs in recombinant inbred strains, they mapped a second locus, called by them N-myc-2, to mouse chromosome 5. The locus on chromosome 5 may be a pseudogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2654812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Regulation of MYCN</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Manohar, C. F., Short, M. L., Nguyen, A., Nguyen, N. N., Chagnovich, D., Yang, Q., Cohn, S. L. <strong>HuD, a neuronal-specific RNA-binding protein, increases the in vivo stability of MYCN RNA.</strong> J. Biol. Chem. 277: 1967-1973, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11711535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11711535</a>] [<a href="https://doi.org/10.1074/jbc.M106966200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11711535">Manohar et al. (2002)</a> identified at least 4 cis-acting destabilizing elements within the MYCN 3-prime UTR, and they found that HUD (ELAVL4; <a href="/entry/168360">168360</a>) binding to this region stabilized MYCN mRNA in cells. Ectopic overexpression of HUD in mouse fibroblasts dramatically inhibited decay of a reporter RNA fused to either full-length MYCN 3-prime UTR or to cis-acting destabilizing elements harboring HUD-binding sites. <a href="#21" class="mim-tip-reference" title="Manohar, C. F., Short, M. L., Nguyen, A., Nguyen, N. N., Chagnovich, D., Yang, Q., Cohn, S. L. <strong>HuD, a neuronal-specific RNA-binding protein, increases the in vivo stability of MYCN RNA.</strong> J. Biol. Chem. 277: 1967-1973, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11711535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11711535</a>] [<a href="https://doi.org/10.1074/jbc.M106966200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11711535">Manohar et al. (2002)</a> suggested that HUD may contribute to the malignant phenotype of neuroblastoma cells by stabilizing MYCN mRNA, thereby enhancing steady-state levels of expression of this oncogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11711535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By database analysis, <a href="#40" class="mim-tip-reference" title="Wei, J. S., Song, Y. K., Durinck, S., Chen, Q.-R., Cheuk, A. T. C., Tsang, P., Zhang, Q., Thiele, C. J., Slack, A., Shohet, J., Khan, J. <strong>The MYCN oncogene is a direct target of miR-34a.</strong> Oncogene 27: 5204-5213, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18504438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18504438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18504438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2008.154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18504438">Wei et al. (2008)</a> found that 5 microRNA (miRNA) genes map to a region of chromosome 1p36 that is often deleted in neuroblastomas. Three of these miRNAs, MIR200B (<a href="/entry/612091">612091</a>), MIR429 (<a href="/entry/612094">612094</a>), and MIR34A (<a href="/entry/611172">611172</a>), were predicted to target the MYCN gene. <a href="#40" class="mim-tip-reference" title="Wei, J. S., Song, Y. K., Durinck, S., Chen, Q.-R., Cheuk, A. T. C., Tsang, P., Zhang, Q., Thiele, C. J., Slack, A., Shohet, J., Khan, J. <strong>The MYCN oncogene is a direct target of miR-34a.</strong> Oncogene 27: 5204-5213, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18504438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18504438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18504438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2008.154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18504438">Wei et al. (2008)</a> found that transfection of MIR34A, but not MIR200B or MIR429, significantly reduced cell growth in IMR32 human fibroblasts and LAN5 human neuroblastoma cells, both of which overexpress MYCN. Western blot analysis showed that transfection of IMR32 and LAN5 cells with MIR34A significantly reduced MYCN expression. MIR34A also induced apoptosis in IMR32 cells. Reporter gene assays confirmed that MIR34A directly targeted the MYCN 3-prime UTR. RT-PCR revealed reduced MIR34A expression in 8 primary neuroblastomas with 1p36 deletion compared with those with normal copy number, and 7 of these showed MYCN overexpression. <a href="#40" class="mim-tip-reference" title="Wei, J. S., Song, Y. K., Durinck, S., Chen, Q.-R., Cheuk, A. T. C., Tsang, P., Zhang, Q., Thiele, C. J., Slack, A., Shohet, J., Khan, J. <strong>The MYCN oncogene is a direct target of miR-34a.</strong> Oncogene 27: 5204-5213, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18504438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18504438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18504438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2008.154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18504438">Wei et al. (2008)</a> concluded that MIR34A suppresses MYCN expression and has a role in limiting cell growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18504438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Antisense Transcription of MYCN</em></strong></p><p>
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Nuclear runoff transcription studies by <a href="#18" class="mim-tip-reference" title="Krystal, G. W., Armstrong, B. C., Battey, J. F. <strong>N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts.</strong> Molec. Cell. Biol. 10: 4180-4191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695323</a>] [<a href="https://doi.org/10.1128/mcb.10.8.4180-4191.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695323">Krystal et al. (1990)</a> revealed sense and antisense transcription across exon 1 of the NMYC locus. They determined that both polyadenylated and nonpolyadenylated antisense transcripts (NCYM; <a href="/entry/605374">605374</a>) are stable and that the nonpolyadenylated NCYM transcripts have 5-prime ends complementary to the 5-prime ends of the NMYC sense mRNA. Using a double RNase protection assay to analyze a human small cell lung cancer cell line, <a href="#18" class="mim-tip-reference" title="Krystal, G. W., Armstrong, B. C., Battey, J. F. <strong>N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts.</strong> Molec. Cell. Biol. 10: 4180-4191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695323</a>] [<a href="https://doi.org/10.1128/mcb.10.8.4180-4191.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695323">Krystal et al. (1990)</a> found that most of the cytoplasmic nonpolyadenylated NCYM RNA existed in an RNA-RNA duplex with about 5% of the sense NMYC mRNA. Duplex formation appeared to occur with only a subset of the multiple forms of the NMYC mRNA, with the transcriptional initiation site of the sense NMYC RNA playing a role in determining this selectivity. Most duplexes included both exon 1 and intron 1 sequences of NMYC, and <a href="#18" class="mim-tip-reference" title="Krystal, G. W., Armstrong, B. C., Battey, J. F. <strong>N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts.</strong> Molec. Cell. Biol. 10: 4180-4191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695323</a>] [<a href="https://doi.org/10.1128/mcb.10.8.4180-4191.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695323">Krystal et al. (1990)</a> hypothesized that duplex formation may modulate RNA processing by preserving a population of NMYC mRNA that retains intron 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Armstrong, B. C., Krystal, G. W. <strong>Isolation and characterization of complementary DNA for N-cym, a gene encoded by the DNA strand opposite to N-myc.</strong> Cell Growth Differ. 3: 385-390, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1419902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1419902</a>]" pmid="1419902">Armstrong and Krystal (1992)</a> cloned the NCYM gene, which overlaps with MYCN and is transcribed from the opposite DNA strand. The 2 genes appeared to be coregulated in tumor cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1419902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Amplification and Overexpression of MYCN in Neuroblastomas</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Kohl, N. E., Kanda, N., Schreck, R. R., Bruns, G., Latt, S. A., Gilbert, F., Alt, F. W. <strong>Transposition and amplification of oncogene-related sequences in human neuroblastomas.</strong> Cell 35: 359-367, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6197179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6197179</a>] [<a href="https://doi.org/10.1016/0092-8674(83)90169-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6197179">Kohl et al. (1983)</a> found that NMYC was amplified 25- to 700-fold in 8 of 9 human neuroblastoma (<a href="/entry/256700">256700</a>) cell lines that contained either homogeneous staining regions (HSR) or double minutes (DM), the karyologic manifestations of amplified genes. (The ninth cell line showed 30-fold amplification of the MYC oncogene.) Although NMYC is located on the short arm of chromosome 2, none of the 5 HSR-containing cell lines had HSRs on chromosome 2. Amplification of the NMYC gene also occurred in retinoblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6197179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Kohl, N. E., Gee, C. E., Alt, F. W. <strong>Activated expression of the N-myc gene in human neuroblastomas and related tumors.</strong> Science 226: 1335-1337, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6505694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6505694</a>] [<a href="https://doi.org/10.1126/science.6505694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6505694">Kohl et al. (1984)</a> found amplified expression of NMYC in neuroblastoma cell lines, but not in other human tumor cell lines, with the exception of a retinoblastoma cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6505694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Emanuel, B. S., Balaban, G., Boyd, J. P., Grossman, A., Negishi, M., Parmiter, A., Glick, M. C. <strong>N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas.</strong> Proc. Nat. Acad. Sci. 82: 3736-3740, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2582423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2582423</a>] [<a href="https://doi.org/10.1073/pnas.82.11.3736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2582423">Emanuel et al. (1985)</a> and others have shown that neuroblastoma cell lines show HSRs at various sites, that the NMYC oncogene is amplified at several of these sites, and that there is apparently no preferred site for NMYC integration and amplification. <a href="#9" class="mim-tip-reference" title="Emanuel, B. S., Balaban, G., Boyd, J. P., Grossman, A., Negishi, M., Parmiter, A., Glick, M. C. <strong>N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas.</strong> Proc. Nat. Acad. Sci. 82: 3736-3740, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2582423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2582423</a>] [<a href="https://doi.org/10.1073/pnas.82.11.3736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2582423">Emanuel et al. (1985)</a> stated that there was no direct evidence of amplification with HSR formation at 2p24-p23, the site of the NMYC gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2582423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Reviewing gene amplification in neuroblastomas, <a href="#4" class="mim-tip-reference" title="Brodeur, G. M., Seeger, R. C. <strong>Gene amplification in human neuroblastomas: basic mechanisms and clinical implications.</strong> Cancer Genet. Cytogenet. 19: 101-111, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3940169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3940169</a>] [<a href="https://doi.org/10.1016/0165-4608(86)90377-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3940169">Brodeur and Seeger (1986)</a> reported that they and other researchers had shown that most DM- and HSR-bearing neuroblastoma cell lines have multiple copies of NMYC. The amplification probably takes place at the level of the extrachromosomal DM, which appear to represent circular molecules, with subsequent linear integration into HSR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3940169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Amplification of the MYCN gene is frequently seen either in extrachromosomal double minutes or in homogeneously staining regions in chromosomes of aggressively growing neuroblastomas. HSRs have never been observed at 2p24-p23, the map location of the MYCN gene. <a href="#8" class="mim-tip-reference" title="Corvi, R., Amler, L. C., Savelyeva, L., Gehring, M., Schwab, M. <strong>MYCN is retained in single copy at chromosome 2 band p23-24 during amplification in human neuroblastoma cells.</strong> Proc. Nat. Acad. Sci. 91: 5523-5527, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202521</a>] [<a href="https://doi.org/10.1073/pnas.91.12.5523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202521">Corvi et al. (1994)</a> used fluorescence in situ hybridization in the study of 5 human neuroblastoma cell lines to demonstrate that, in addition to amplified MYCN in HSRs or double minutes, single-copy MYCN was present at the normal position on chromosome 2. In 1 cell line there was coamplification of MYCN together with DNA of the host chromosome 12 to which MYCN had been transposed. The results suggested that the initial event is transposition of MYCN, with retention of the normal gene in its position on 2p before the occurrence of amplification. Thus, the mechanisms of amplified MYCN are probably different from those leading to amplification of drug-resistance genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#29" class="mim-tip-reference" title="Reiter, J. L., Brodeur, G. M. <strong>High-resolution mapping of a 130-kb core region of the MYCN amplicon in neuroblastomas.</strong> Genomics 32: 97-103, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8786126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8786126</a>] [<a href="https://doi.org/10.1006/geno.1996.0081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8786126">Reiter and Brodeur (1996)</a> generated a high-resolution restriction map of approximately 500 kb spanning the MYCN locus. They found that deletions and rearrangements of the amplicon occurred less often in primary tumors than in cell lines. They also defined a 130-kb common core region of the MYCN amplicon that was amplified in 32 of 33 neuroblastomas. The authors proposed that despite the large size of most MYCN amplicons, the core region that is consistently amplified in neuroblastomas probably contains the MYCN gene and little else. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8786126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Guo, C., White, P. S., Weiss, M. J., Hogarty, M. D., Thompson, P. M., Stram, D. O., Gerbing, R., Matthay, K. K., Seeger, R. C., Brodeur, G. M., Maris, J. M. <strong>Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas.</strong> Oncogene 18: 4948-4957, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10490829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10490829</a>] [<a href="https://doi.org/10.1038/sj.onc.1202887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10490829">Guo et al. (1999)</a> performed a comprehensive analysis of deletions of 11q in neuroblastomas: 295 sporadic, 15 familial, and 21 tumor-derived cell lines. Loss of heterozygosity (LOH) analysis was performed at 24 microsatellite loci spanning 11q. LOH was observed at multiple 11q loci in 129 of 295 (44%) sporadic neuroblastomas, 5 of 15 (33%) familial neuroblastomas, and 5 of 21 (24%) neuroblastoma cell lines. A single region of 2.1 cM within 11q23.3, flanked by markers D11S1340 and D11S1299, was deleted in all specimens with 11q LOH. Allelic loss at 11q23 was inversely related to MYCN amplification (P less than 0.001). Within the subset of cases with a single copy of MYCN, 11q LOH was associated with advanced stage disease, unfavorable histopathology, and decreased overall survival probability. However, 11q LOH was not independently prognostic in multivariate analyses. These data were judged to support the hypothesis that a tumor suppressor gene mapping within 11q23.3 is commonly inactivated during the malignant evolution of a large subset of neuroblastomas, especially those with unamplified MYCN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10490829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Molenaar, J. J., Domingo-Fernandez, R., Ebus, M. E., Lindner, S., Koster, J., Drabek, K., Mestdagh, P., van Sluis, P., Valentijn, L. J., van Nes, J., Broekmans, M., Haneveld, F., and 18 others. <strong>LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression.</strong> Nature Genet. 44: 1199-1206, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23042116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23042116</a>] [<a href="https://doi.org/10.1038/ng.2436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23042116">Molenaar et al. (2012)</a> reported that LIN28B (<a href="/entry/611044">611044</a>) showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the LET7 (see <a href="/entry/605386">605386</a>) miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-LET7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which Lin28b expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low Let7 miRNA levels and high Mycn protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23042116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Liu, P. Y., Erriquez, D., Marshall, G. M., Tee, A. E., Polly, P., Wong, M., Liu, B., Bell, J. L., Zhang, X. D., Milazzo, G., Cheung, B. B., Fox, A., Swarbrick, A., Huttelmaier, S., Kavallaris, M., Perini, G., Mattick, J. S., Dinger, M. E., Liu, T. <strong>Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression.</strong> J. Nat. Cancer Inst. 106: dju113, 2014. Note: Electronic Article. Erratum published online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24906397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24906397</a>] [<a href="https://doi.org/10.1093/jnci/dju113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24906397">Liu et al. (2014)</a> identified a long noncoding RNA, lncUSMYCN (MYCNUT; <a href="/entry/615968">615968</a>), upstream of the MYCN gene within the 130-kb region of chromosome 2 frequently amplified in neuroblastomas. They found that lncUSMYCN was coamplified with MYCN in a subset of primary neuroblastomas and neuroblastoma cell lines. Expression of lncUSMYCN was upregulated in only a few neuroblastomas that did not show MYCN amplification. Knockdown of lncUSMYCN via small interfering RNA reduced MYCN mRNA expression in a human neuroblastoma cell line, and ectopic expression of lncUSMYCN upregulated exogenous MYCN mRNA and induced cell proliferation. Unlike other lncRNAs, lncUSMYCN did not directly modulate MYCN promoter activity, but it bound directly to the RNA-binding protein NONO (<a href="/entry/300084">300084</a>), which then increased MYCN expression. High lncUSMYCN or NONO expression in neuroblastoma tissue independently predicted poor patient prognosis. Knockdown of lncUSMYCN reduced tumor growth in neuroblastoma-bearing mice. <a href="#20" class="mim-tip-reference" title="Liu, P. Y., Erriquez, D., Marshall, G. M., Tee, A. E., Polly, P., Wong, M., Liu, B., Bell, J. L., Zhang, X. D., Milazzo, G., Cheung, B. B., Fox, A., Swarbrick, A., Huttelmaier, S., Kavallaris, M., Perini, G., Mattick, J. S., Dinger, M. E., Liu, T. <strong>Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression.</strong> J. Nat. Cancer Inst. 106: dju113, 2014. Note: Electronic Article. Erratum published online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24906397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24906397</a>] [<a href="https://doi.org/10.1093/jnci/dju113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24906397">Liu et al. (2014)</a> concluded that lncUSMYCN and NONO play important roles in regulating MYCN expression and neuroblastoma oncogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24906397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MYCN-amplified neuroblastoma cell lines, <a href="#27" class="mim-tip-reference" title="Powers, J. T., Tsanov, K. M., Pearson, D. S., Roels, F., Spina, C. S., Ebright, R., Seligson, M., de Soysa, Y., Cahan, P., Theissen, J., Tu, H.-C., Han, A., Kurek, K. C., LaPier, G. S., Osborne, J. K., Ross, S. J., Cesana, M., Collins, J. J., Berthold, F., Daley, G. Q. <strong>Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.</strong> Nature 535: 246-251, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27383785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27383785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27383785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature18632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27383785">Powers et al. (2016)</a> showed that LIN28B is dispensable, despite derepression of LET7. <a href="#27" class="mim-tip-reference" title="Powers, J. T., Tsanov, K. M., Pearson, D. S., Roels, F., Spina, C. S., Ebright, R., Seligson, M., de Soysa, Y., Cahan, P., Theissen, J., Tu, H.-C., Han, A., Kurek, K. C., LaPier, G. S., Osborne, J. K., Ross, S. J., Cesana, M., Collins, J. J., Berthold, F., Daley, G. Q. <strong>Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.</strong> Nature 535: 246-251, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27383785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27383785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27383785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature18632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27383785">Powers et al. (2016)</a> demonstrated that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge LET7, which reconciles the dispensability of LIN28B. The authors found that genetic loss of LET7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. <a href="#27" class="mim-tip-reference" title="Powers, J. T., Tsanov, K. M., Pearson, D. S., Roels, F., Spina, C. S., Ebright, R., Seligson, M., de Soysa, Y., Cahan, P., Theissen, J., Tu, H.-C., Han, A., Kurek, K. C., LaPier, G. S., Osborne, J. K., Ross, S. J., Cesana, M., Collins, J. J., Berthold, F., Daley, G. Q. <strong>Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.</strong> Nature 535: 246-251, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27383785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27383785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27383785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature18632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27383785">Powers et al. (2016)</a> proposed that LET7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27383785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Finegold Syndrome 1</em></strong></p><p>
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Feingold syndrome-1 (FGLDS1; <a href="/entry/164280">164280</a>) is an autosomal dominant disorder characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly, and cardiac defect. <a href="#39" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T., Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R. A., Chaing, C., Brunner, H. G. <strong>MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.</strong> Nature Genet. 37: 465-467, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821734</a>] [<a href="https://doi.org/10.1038/ng1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15821734">Van Bokhoven et al. (2005)</a> carried out haplotype analysis in a previously unreported family with Feingold syndrome and confirmed linkage to the previously identified 7.3-cM locus on chromosome 2p24-p23 (Celli et al. (<a href="#6" class="mim-tip-reference" title="Celli, J., van Beusekom, E., Hennekam, R. C. M., Gallardo, M. E., Smeets, D. F. C. M., Rodriguez de Cordoba, S., Innis, J. W., Frydman, M., Konig, R., Kingston, H., Tolmie, J., Govaerts, L. C. P., van Bokhoven H., Brunner, H. G. <strong>Familial syndromic esophageal atresia maps to 2p23-p24.</strong> Am. J. Hum. Genet. 66: 436-444, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677303</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677303[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/10.1086/302779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677303">2000</a>, <a href="#7" class="mim-tip-reference" title="Celli, J., van Bokhoven, H., Brunner, H. G. <strong>Feingold syndrome: clinical review and genetic mapping.</strong> Am. J. Med. Genet. 122A: 294-300, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14518066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14518066</a>] [<a href="https://doi.org/10.1002/ajmg.a.20471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14518066">2003</a>)). Affected members carried a microdeletion of maximally 1.2 Mb, encompassing MYCN but no other known or predicted gene, making it an excellent candidate for Feingold syndrome. In a cohort of 23 unrelated families with Feingold syndrome, <a href="#39" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T., Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R. A., Chaing, C., Brunner, H. G. <strong>MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.</strong> Nature Genet. 37: 465-467, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821734</a>] [<a href="https://doi.org/10.1038/ng1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15821734">van Bokhoven et al. (2005)</a> sequenced the MYCN gene and identified 12 different heterozygous mutations in 15 families, 6 of which occurred de novo. Most mutations created stop codons or frameshifts in the 3-prime end of the open reading frame just before or in the regions encoding the basic helix-loop-helix and leucine-zipper domains. The authors identified 3 different missense mutations at 2 adjacent arginine residues (<a href="#0001">164840.0001</a>-<a href="#0003">164840.0003</a>). These arginines are at the core of the basic helix-loop-helix domain and are strictly conserved among members of the Myc family. The corresponding arginines in MYC (<a href="/entry/190080">190080</a>), arg366 and arg367, are crucial for DNA binding. Conservation of these residues suggests that they have a similar role in MYCN. Complete deletion of the MYCN gene was observed in 2 families, indicating that MYCN haploinsufficiency gives rise to a phenotype comparable to that observed for the other mutations and suggesting that these alleles are effectively null. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15821734+14518066+10677303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Marcelis, C. L. M., Hol, F. A., Graham, G. E., Rieu, P. N. M. A., Kellermayer, R., Meijer, R. P. P., Lugtenberg, D., Scheffer, H., van Bokhoven, H., Brunner, H. G., de Brouwer, A. P. M. <strong>Genotype-phenotype correlations in MYCN-related Feingold syndrome.</strong> Hum. Mutat. 29: 1125-1132, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18470948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18470948</a>] [<a href="https://doi.org/10.1002/humu.20750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18470948">Marcelis et al. (2008)</a> analyzed the MYCN gene in 93 patients from 50 families with a strong clinical suspicion of Feingold syndrome and identified 16 heterozygous mutations in 17 families with a total of 26 patients, including mutations in exon 2, which had not previously been reported (see, e.g., <a href="#0007">164840.0007</a>). The authors reviewed the clinical features of the 77 mutation-positive patients reported to date and compared them with the largest previous overview (<a href="#7" class="mim-tip-reference" title="Celli, J., van Bokhoven, H., Brunner, H. G. <strong>Feingold syndrome: clinical review and genetic mapping.</strong> Am. J. Med. Genet. 122A: 294-300, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14518066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14518066</a>] [<a href="https://doi.org/10.1002/ajmg.a.20471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14518066">Celli et al., 2003</a>), noting that digital anomalies involving brachymesophalangy and toe syndactyly were the most consistent features, present in 100% and 97% of patients, respectively, whereas small head circumference was present in 89% of cases. Gastrointestinal atresia was the most important major congenital anomaly (55%), but renal and cardiac anomalies were also frequent (18% and 15%, respectively). <a href="#22" class="mim-tip-reference" title="Marcelis, C. L. M., Hol, F. A., Graham, G. E., Rieu, P. N. M. A., Kellermayer, R., Meijer, R. P. P., Lugtenberg, D., Scheffer, H., van Bokhoven, H., Brunner, H. G., de Brouwer, A. P. M. <strong>Genotype-phenotype correlations in MYCN-related Feingold syndrome.</strong> Hum. Mutat. 29: 1125-1132, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18470948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18470948</a>] [<a href="https://doi.org/10.1002/humu.20750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18470948">Marcelis et al. (2008)</a> suggested that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18470948+14518066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Megalencephaly-Polydactyly Syndrome</em></strong></p><p>
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In a patient with megalencephaly-polydactyly syndrome (MPAPA; <a href="/entry/620748">620748</a>), <a href="#14" class="mim-tip-reference" title="Kato, K., Miya, F., Hamada, N., Negishi, Y., Narumi-Kishimoto, Y., Ozawa, H., Ito, H., Hori, I., Hattori, A., Okamoto, N., Kato, M., Tsunoda, T., Kanemura, Y., Kosaki, K., Takahashi, Y., Nagata, K. I., Saitoh, S. <strong>MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.</strong> J. Med. Genet. 56: 388-395, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30573562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30573562</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30573562">Kato et al. (2019)</a> identified a de novo heterozygous mutation in the MYCN gene (T58M; <a href="#0008">164840.0008</a>). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Expression of MYCN with the T58M mutation in HEK293 cells demonstrated that the protein was hypophosphorylated compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30573562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 patients with MPAPA, <a href="#26" class="mim-tip-reference" title="Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S. <strong>Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.</strong> Hum. Genet. Genomics Adv. 4: 100238, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37710961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37710961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37710961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2023.100238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37710961">Nishio et al. (2023)</a> identified de novo heterozygous missense mutations in the MYCN gene: the previously identified T58M mutation and P60L (<a href="#0009">164840.0009</a>). Expression of MYCN with each mutation in HEK293 cells resulted in decreased phosphorylation at T58 compared to wildtype. MYCN with the T58M mutation was also more stable compared to wildtype. Both mutants were able to activate transcription of downstream genes. <a href="#26" class="mim-tip-reference" title="Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S. <strong>Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.</strong> Hum. Genet. Genomics Adv. 4: 100238, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37710961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37710961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37710961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2023.100238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37710961">Nishio et al. (2023)</a> concluded that T58M and P60L are gain-of-function mutations, which result in a mirror phenotype of Feingold syndrome-1 (<a href="/entry/164280">164280</a>), which results from loss-of-function mutations in MYCN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37710961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Nmyc is a downstream target of Shh (<a href="/entry/600725">600725</a>) signaling and promotes rapid cell division of granule neuron progenitors (GNPs) in mice. Nmyc overexpression can enforce proliferation of GNPs independently of Shh signaling, and conversely, its conditional loss during embryonic cerebellar development results in severe GNP deficiency, perturbs foliation, and leads to reduced cerebellar mass. <a href="#41" class="mim-tip-reference" title="Zindy, F., Knoepfler, P. S., Xie, S., Sherr, C. J., Eisenman, R. N., Roussel, M. F. <strong>N-Myc and the cyclin-dependent kinase inhibitors p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development.</strong> Proc. Nat. Acad. Sci. 103: 11579-11583, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864777[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.0604727103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864777">Zindy et al. (2006)</a> found that Myc mRNA levels increased in Nmyc-null mouse GNPs and that simultaneous deletion of both Myc and Nmyc exacerbated defective cerebellar development. Since Nmyc loss triggers precocious expression of the cyclin-dependent kinase inhibitors Kip1 (CDKN1B; <a href="/entry/600778">600778</a>) and Ink4c (CDKN2C; <a href="/entry/603369">603369</a>) in the cerebellar primordium, <a href="#41" class="mim-tip-reference" title="Zindy, F., Knoepfler, P. S., Xie, S., Sherr, C. J., Eisenman, R. N., Roussel, M. F. <strong>N-Myc and the cyclin-dependent kinase inhibitors p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development.</strong> Proc. Nat. Acad. Sci. 103: 11579-11583, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864777[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.0604727103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864777">Zindy et al. (2006)</a> disrupted Kip1 and Ink4c in Nmyc-null cerebella and found that this partially rescued GNP cell proliferation and cerebellar foliation. They concluded that expression of NMYC and concomitant downregulation of INK4C and KIP1 contribute to the proper development of the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16864777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Martins, R. A. P., Zindy, F., Donovan, S., Zhang, J., Pounds, S., Wey, A., Knoepfler, P. S., Eisenman, R. N., Roussel, M. F., Dyer, M. A. <strong>N-myc coordinates retinal growth with eye size during mouse development.</strong> Genes Dev. 22: 179-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18198336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18198336</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18198336[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.1608008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18198336">Martins et al. (2008)</a> found that mouse Nmyc was expressed in retinal progenitor cells, where it regulated proliferation in a cell-autonomous manner, and that it coordinated growth of the retina and eye. Retinas of Nmyc-deficient mice were hypocellular, but they were precisely proportioned to the size of the eye. Nmyc repressed expression of the cyclin-dependent kinase inhibitor p27(Kip1), but acted independently of cyclin D1 (<a href="/entry/168461">168461</a>). Acute inactivation of Nmyc led to increased expression of p27(Kip1), and simultaneous inactivation of p27(Kip1) and Nmyc rescued the hypocellular phenotype of Nmyc-deficient retinas. Nmyc was not required for retinal cell fate specification, differentiation, or survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18198336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S. <strong>Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.</strong> Hum. Genet. Genomics Adv. 4: 100238, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37710961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37710961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37710961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2023.100238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37710961">Nishio et al. (2023)</a> generated a mouse model with a heterozygous T58M mutation in the Mycn gene (T58M/WT) and a mouse model with a heterozygous frameshift mutation in exon 1 of the Mycn gene (FS/WT). The heterozygous T58M/WT mice had polydactyly and higher brain weights compared to FS/WT and WT mice, whereas FS/WT had lower brain weights than WT mice. Histologic examination of brains from the mutant mice showed that the T58M/WT mice had thicker cerebral cortex layers and FS/WT mice had thinner cerebral cortex layers at the primary motor cortex. Further studies suggested overproliferation of neural progenitors in the T58M/WT mice and underproliferation of neural progenitors in the FS/WT mice during early development. Additionally, T58M/WT had a variety of kidney abnormalities, including larger kidneys, unilateral kidny, and dilation of renal convoluted tubules, compared to WT and FS/WT mice. T58M/WT female mice were infertile and were found to have various uterovaginal malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37710961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=164840[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893646;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014906 OR RCV001564807 OR RCV001849263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014906, RCV001564807, RCV001849263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014906...</a>
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<p>In affected members of 2 families with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#39" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T., Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R. A., Chaing, C., Brunner, H. G. <strong>MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.</strong> Nature Genet. 37: 465-467, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821734</a>] [<a href="https://doi.org/10.1038/ng1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15821734">van Bokhoven et al. (2005)</a> identified a heterozygous 1178G-A transition in the MYCN gene, resulting in an arg393-to-his (R393H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15821734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893647 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893647;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#39" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T., Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R. A., Chaing, C., Brunner, H. G. <strong>MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.</strong> Nature Genet. 37: 465-467, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821734</a>] [<a href="https://doi.org/10.1038/ng1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15821734">van Bokhoven et al. (2005)</a> identified a heterozygous 1177C-A transversion in the MYCN gene, resulting in an arg393-to-ser (R393S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15821734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893648 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893648;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014908 OR RCV005089257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014908, RCV005089257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014908...</a>
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<p>In affected members of a family with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#39" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T., Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R. A., Chaing, C., Brunner, H. G. <strong>MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.</strong> Nature Genet. 37: 465-467, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821734</a>] [<a href="https://doi.org/10.1038/ng1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15821734">van Bokhoven et al. (2005)</a> identified a heterozygous 1181G-A transition in the MYCN gene, resulting in an arg394-to-his (R394H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15821734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs113994115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994115;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113994115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs113994115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014910" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014910" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014910</a>
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<p>In a 4-year-old boy with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#38" class="mim-tip-reference" title="Teszas, A., Meijer, R., Scheffer, H., Gyuris, P., Kosztolanyi, G., van Bokhoven, H., Kellermayer, R. <strong>Expanding the clinical spectrum of MYCN-related Feingold syndrome.</strong> Am. J. Med. Genet. 140A: 2254-2256, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16906565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16906565</a>] [<a href="https://doi.org/10.1002/ajmg.a.31407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16906565">Teszas et al. (2006)</a> identified a heterozygous 217G-T transversion in exon 2 of the MYCN gene, resulting in a glu73-to-ter (E73X) substitution. The patient's mother and grandmother both carried the mutation and had less severe clinical anomalies including microcephaly and digital abnormalities with normal intelligence. <a href="#38" class="mim-tip-reference" title="Teszas, A., Meijer, R., Scheffer, H., Gyuris, P., Kosztolanyi, G., van Bokhoven, H., Kellermayer, R. <strong>Expanding the clinical spectrum of MYCN-related Feingold syndrome.</strong> Am. J. Med. Genet. 140A: 2254-2256, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16906565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16906565</a>] [<a href="https://doi.org/10.1002/ajmg.a.31407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16906565">Teszas et al. (2006)</a> suggested that disorder in the mother and grandmother represents a milder form of Feingold syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16906565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a proband with Feingold syndrome, <a href="#22" class="mim-tip-reference" title="Marcelis, C. L. M., Hol, F. A., Graham, G. E., Rieu, P. N. M. A., Kellermayer, R., Meijer, R. P. P., Lugtenberg, D., Scheffer, H., van Bokhoven, H., Brunner, H. G., de Brouwer, A. P. M. <strong>Genotype-phenotype correlations in MYCN-related Feingold syndrome.</strong> Hum. Mutat. 29: 1125-1132, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18470948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18470948</a>] [<a href="https://doi.org/10.1002/humu.20750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18470948">Marcelis et al. (2008)</a> identified compound heterozygosity for the E73X mutation and a 64C-T polymorphism, resulting in a gln22-to-ter (Q22X) substitution in exon 1 affecting only the N-terminally truncated 'delta-MYCN' isoform produced by initiation of translation in exon 1. The E73X mutation was found to segregate with disease in the mother and maternal grandmother, whereas the Q22X variant was found in the unaffected father, suggesting that variants involving only delta-MYCN do not contribute to Feingold syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18470948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1558534266 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1558534266;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1558534266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1558534266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014911 OR RCV003228894" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014911, RCV003228894" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014911...</a>
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<p>In a Turkish girl with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#2" class="mim-tip-reference" title="Blaumeiser, B., Oehl-Jaschkowitz, B., Borozdin, W., Kohlhase, J. <strong>Feingold syndrome associated with two novel MYCN mutations in sporadic and familial cases including monozygotic twins. (Letter)</strong> Am. J. Med. Genet. 146A: 2304-2307, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18671284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18671284</a>] [<a href="https://doi.org/10.1002/ajmg.a.32444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18671284">Blaumeiser et al. (2008)</a> identified a de novo heterozygous 1-bp duplication (626dupC) in exon 2 of the MYCN gene, predicted to result in premature termination and nonsense-mediated mRNA decay of the exon 2-3 transcript. Neither unaffected parent carried the mutation. The girl had dysmorphic facial features, developmental delay, and distal limb anomalies. <a href="#2" class="mim-tip-reference" title="Blaumeiser, B., Oehl-Jaschkowitz, B., Borozdin, W., Kohlhase, J. <strong>Feingold syndrome associated with two novel MYCN mutations in sporadic and familial cases including monozygotic twins. (Letter)</strong> Am. J. Med. Genet. 146A: 2304-2307, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18671284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18671284</a>] [<a href="https://doi.org/10.1002/ajmg.a.32444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18671284">Blaumeiser et al. (2008)</a> noted that finding a mutation in exon 2 of the MYCN gene indicated that the MYCN transcript containing exon 2 is necessary for normal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18671284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913666 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913666;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014912 OR RCV004719647" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014912, RCV004719647" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014912...</a>
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<p>In 5 affected members of a 3-generation family with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#2" class="mim-tip-reference" title="Blaumeiser, B., Oehl-Jaschkowitz, B., Borozdin, W., Kohlhase, J. <strong>Feingold syndrome associated with two novel MYCN mutations in sporadic and familial cases including monozygotic twins. (Letter)</strong> Am. J. Med. Genet. 146A: 2304-2307, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18671284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18671284</a>] [<a href="https://doi.org/10.1002/ajmg.a.32444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18671284">Blaumeiser et al. (2008)</a> identified a heterozygous 1145G-A transition in exon 3 of the MYCN gene, resulting in an arg382-to-his (R382H) substitution affecting a residue critical for DNA binding in the helix-loop-helix domain. There was wide phenotypic variability: 3 had mental retardation and finger and toe defects, of whom 1 also had intestinal atresia, whereas the other 2 showed only finger and toe anomalies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18671284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913667 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913667;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014909" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014909" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014909</a>
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<p>In a family with Feingold syndrome (FGLDS1; <a href="/entry/164280">164280</a>), <a href="#22" class="mim-tip-reference" title="Marcelis, C. L. M., Hol, F. A., Graham, G. E., Rieu, P. N. M. A., Kellermayer, R., Meijer, R. P. P., Lugtenberg, D., Scheffer, H., van Bokhoven, H., Brunner, H. G., de Brouwer, A. P. M. <strong>Genotype-phenotype correlations in MYCN-related Feingold syndrome.</strong> Hum. Mutat. 29: 1125-1132, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18470948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18470948</a>] [<a href="https://doi.org/10.1002/humu.20750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18470948">Marcelis et al. (2008)</a> identified a heterozygous 231G-A transition in exon 2 of the MYCN gene, resulting in a trp77-to-ter (W77X) substitution that segregated with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18470948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003234238 OR RCV003410288 OR RCV004721157" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003234238, RCV003410288, RCV004721157" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003234238...</a>
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<p>In a 15-year-old boy with megalencephaly-polydactyly syndrome (MPAPA; <a href="/entry/620748">620748</a>), who was negative for mutations in known megalencephaly genes, <a href="#14" class="mim-tip-reference" title="Kato, K., Miya, F., Hamada, N., Negishi, Y., Narumi-Kishimoto, Y., Ozawa, H., Ito, H., Hori, I., Hattori, A., Okamoto, N., Kato, M., Tsunoda, T., Kanemura, Y., Kosaki, K., Takahashi, Y., Nagata, K. I., Saitoh, S. <strong>MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.</strong> J. Med. Genet. 56: 388-395, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30573562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30573562</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30573562">Kato et al. (2019)</a> identified a de novo heterozygous c.173C-T transition (c.173C-T, NM_005378.5) in the MYCN gene, resulting in a thr58-to-met (T58M) substitution. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Expression of MYCN with the T58M mutation in HEK293 cells demonstrated that the protein was hypophosphorylated compared to wildtype. When MYCN with the T58M mutation was electroporated into mouse neuronal progenitor stem cells, the mutant Mycn was shown to be more stable and to induce higher levels of expression of Ccnd1 (<a href="/entry/168461">168461</a>) and Ccnd2 (<a href="/entry/123833">123833</a>) compared to wildtype Mycn. <a href="#14" class="mim-tip-reference" title="Kato, K., Miya, F., Hamada, N., Negishi, Y., Narumi-Kishimoto, Y., Ozawa, H., Ito, H., Hori, I., Hattori, A., Okamoto, N., Kato, M., Tsunoda, T., Kanemura, Y., Kosaki, K., Takahashi, Y., Nagata, K. I., Saitoh, S. <strong>MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.</strong> J. Med. Genet. 56: 388-395, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30573562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30573562</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30573562">Kato et al. (2019)</a> hypothesized that the T58M mutation resulted in a gain-of-function and stabilization of the MYCN protein. The increased accumulation of MYCN protein potentially prolonged expression of CCND1 and CCND2 and promoted neurogenesis in the developing cortex and thus megalencephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30573562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an 8-month-old Japanese boy (patient 2), born of nonconsanguineous parents, with MPAPA, <a href="#26" class="mim-tip-reference" title="Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S. <strong>Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.</strong> Hum. Genet. Genomics Adv. 4: 100238, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37710961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37710961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37710961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2023.100238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37710961">Nishio et al. (2023)</a> identified heterozygosity for the T58M mutation in the MYCN gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. MYCN with the T58M mutation was expressed in HEK293 cells and the level of phosphorylation at T58 was decreased compared to wildtype. MYCN with the T58M mutation was also more stable compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37710961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 MEGALENCEPHALY-POLYDACTYLY SYNDROME</strong>
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MYCN, PRO60LEU
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003154630 OR RCV003889282" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003154630, RCV003889282" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003154630...</a>
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<p>In a fetus (patient 1), conceived of nonconsanguineous French parents, with megalencephaly-polydactyly syndrome (MPAPA; <a href="/entry/620748">620748</a>), <a href="#26" class="mim-tip-reference" title="Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S. <strong>Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.</strong> Hum. Genet. Genomics Adv. 4: 100238, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37710961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37710961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37710961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2023.100238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37710961">Nishio et al. (2023)</a> identified heterozygosity for a c.179C-T transition (c.179C-T, NM_005378.6) in the MYCN gene, resulting in a pro60-to-leu (P60L) substitution. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. The mutation was not present in the gnomAD database. MYCN with the P60L mutation was expressed in HEK293 cells and the level of phosphorylation at T58 was decreased compared to wildtype. MYCN with the P60L mutation was also more stable compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37710961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Brodeur1984" class="mim-tip-reference" title="Brodeur, G. M., Seeger, R. C., Schwab, M., Varmus, H. E., Bishop, J. M. <strong>Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.</strong> Science 224: 1121-1124, 1984.">Brodeur et al. (1984)</a>; <a href="#Kohl1986" class="mim-tip-reference" title="Kohl, N. E., Legouy, E., DePinho, R. A., Nisen, P. D., Smith, R. K., Gee, C. E., Alt, F. W. <strong>Human N-myc is closely related in organization and nucleotide sequence to c-myc.</strong> Nature 319: 73-77, 1986.">Kohl et al. (1986)</a>; <a href="#Lee1984" class="mim-tip-reference" title="Lee, W.-H., Murphree, A. L., Benedict, W. F. <strong>Expression and amplification of the N-myc gene in primary retinoblastoma.</strong> Nature 309: 458-460, 1984.">Lee et al. (1984)</a>; <a href="#Schwab1983" class="mim-tip-reference" title="Schwab, M., Alitalo, K., Klempnauer, K.-H., Varmus, H. E., Bishop, J. M., Gilbert, F., Brodeur, G., Goldstein, M., Trent, J. <strong>Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.</strong> Nature 305: 245-248, 1983.">Schwab
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et al. (1983)</a>; <a href="#Schwab1984" class="mim-tip-reference" title="Schwab, M., Varmus, H. E., Bishop, J. M., Grzeschik, K.-H., Naylor, S. L., Sakaguchi, A. Y., Brodeur, G., Trent, J. <strong>Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc.</strong> Nature 308: 288-291, 1984.">Schwab et al. (1984)</a>; <a href="#Schwab1985" class="mim-tip-reference" title="Schwab, M. <strong>Amplification of N-myc in human neuroblastomas.</strong> Trends Genet. 1: 271-275, 1985.">Schwab (1985)</a>; <a href="#Seeger1985" class="mim-tip-reference" title="Seeger, R. C., Brodeur, G. M., Sather, H., Dalton, A., Siegel, S. E., Wong, K. Y., Hammond, D. <strong>Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas.</strong> New Eng. J. Med. 313: 1111-1116, 1985.">Seeger et al.
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(1985)</a>; <a href="#Shiloh1985" class="mim-tip-reference" title="Shiloh, Y., Shipley, J., Brodeur, G. M., Bruns, G., Korf, B., Donlon, T., Schreck, R. R., Seeger, R., Sakai, K., Latt, S. A. <strong>Differential amplification, assembly, and relocation of multiple DNA sequences in human neuroblastomas and neuroblastoma cell lines.</strong> Proc. Nat. Acad. Sci. 82: 3761-3765, 1985.">Shiloh et al. (1985)</a>
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Armstrong, B. C., Krystal, G. W.
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<strong>Isolation and characterization of complementary DNA for N-cym, a gene encoded by the DNA strand opposite to N-myc.</strong>
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Cell Growth Differ. 3: 385-390, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1419902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1419902</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1419902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Blaumeiser, B., Oehl-Jaschkowitz, B., Borozdin, W., Kohlhase, J.
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<strong>Feingold syndrome associated with two novel MYCN mutations in sporadic and familial cases including monozygotic twins. (Letter)</strong>
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Am. J. Med. Genet. 146A: 2304-2307, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18671284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18671284</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18671284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32444" target="_blank">Full Text</a>]
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Brodeur, G. M., Seeger, R. C., Schwab, M., Varmus, H. E., Bishop, J. M.
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<strong>Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.</strong>
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Science 224: 1121-1124, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6719137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6719137</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6719137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.6719137" target="_blank">Full Text</a>]
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<strong>Gene amplification in human neuroblastomas: basic mechanisms and clinical implications.</strong>
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Cancer Genet. Cytogenet. 19: 101-111, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3940169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3940169</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3940169" 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/10.1016/0165-4608(86)90377-8" target="_blank">Full Text</a>]
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Campbell, G. R., Zimmerman, K., Blank, R. D., Alt, F. W., D'Eustachio, P.
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<strong>Chromosomal location of N-myc and L-myc genes in the mouse.</strong>
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Oncogene Res. 4: 47-54, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2654812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2654812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2654812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Celli, J., van Beusekom, E., Hennekam, R. C. M., Gallardo, M. E., Smeets, D. F. C. M., Rodriguez de Cordoba, S., Innis, J. W., Frydman, M., Konig, R., Kingston, H., Tolmie, J., Govaerts, L. C. P., van Bokhoven H., Brunner, H. G.
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<strong>Familial syndromic esophageal atresia maps to 2p23-p24.</strong>
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Am. J. Hum. Genet. 66: 436-444, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677303</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677303[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=10677303" 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/10.1086/302779" target="_blank">Full Text</a>]
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Celli, J., van Bokhoven, H., Brunner, H. G.
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<strong>Feingold syndrome: clinical review and genetic mapping.</strong>
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Am. J. Med. Genet. 122A: 294-300, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14518066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14518066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14518066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20471" target="_blank">Full Text</a>]
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Corvi, R., Amler, L. C., Savelyeva, L., Gehring, M., Schwab, M.
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<strong>MYCN is retained in single copy at chromosome 2 band p23-24 during amplification in human neuroblastoma cells.</strong>
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Proc. Nat. Acad. Sci. 91: 5523-5527, 1994.
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[<a href="https://doi.org/10.1038/ng.2436" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864777[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=16864777" 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.0604727103" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/06/2024
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Hilary J. Vernon - updated : 01/13/2023<br>Ada Hamosh - updated : 09/10/2019<br>Patricia A. Hartz - updated : 8/27/2014<br>Ada Hamosh - updated : 1/11/2013<br>Matthew B. Gross - updated : 1/6/2010<br>Patricia A. Hartz - updated : 11/17/2009<br>Marla J. F. O'Neill - updated : 10/20/2009<br>Patricia A. Hartz - updated : 3/12/2008<br>Cassandra L. Kniffin - updated : 12/19/2006<br>Patricia A. Hartz - updated : 10/3/2006<br>Patricia A. Hartz - updated : 5/9/2005<br>Victor A. McKusick - updated : 5/3/2005<br>Dawn Watkins-Chow - updated : 10/31/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Alan F. Scott - updated : 4/11/1996
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Victor A. McKusick : 6/23/1986
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carol : 03/07/2024
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carol : 03/06/2024<br>carol : 01/13/2023<br>carol : 01/28/2021<br>carol : 09/11/2019<br>alopez : 09/10/2019<br>carol : 12/22/2017<br>alopez : 10/18/2017<br>carol : 01/29/2015<br>mgross : 8/27/2014<br>alopez : 1/15/2013<br>alopez : 1/15/2013<br>terry : 1/11/2013<br>carol : 7/21/2011<br>mgross : 1/6/2010<br>mgross : 1/6/2010<br>terry : 11/17/2009<br>wwang : 10/26/2009<br>terry : 10/20/2009<br>ckniffin : 9/18/2009<br>wwang : 1/8/2009<br>ckniffin : 1/5/2009<br>mgross : 3/18/2008<br>terry : 3/12/2008<br>wwang : 12/27/2006<br>ckniffin : 12/19/2006<br>mgross : 10/10/2006<br>terry : 10/3/2006<br>mgross : 5/10/2005<br>terry : 5/9/2005<br>tkritzer : 5/3/2005<br>carol : 10/31/2000<br>carol : 11/16/1999<br>carol : 11/15/1999<br>terry : 11/9/1999<br>alopez : 9/3/1998<br>joanna : 8/9/1996<br>terry : 4/17/1996<br>mark : 4/11/1996<br>terry : 4/11/1996<br>mark : 4/10/1996<br>jason : 6/22/1994<br>pfoster : 3/25/1994<br>warfield : 3/21/1994<br>supermim : 3/16/1992<br>carol : 3/8/1992<br>supermim : 3/20/1990
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<span class="mim-font">
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<strong>*</strong> 164840
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<h3>
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MYCN PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYCN
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<em>Alternative titles; symbols</em>
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V-MYC AVIAN MYELOCYTOMATOSIS VIRAL-RELATED ONCOGENE, NEUROBLASTOMA-DERIVED<br />
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ONCOGENE NMYC<br />
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NMYC ONCOGENE<br />
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AVIAN MYELOCYTOMATOSIS VIRAL-RELATED ONCOGENE, NEUROBLASTOMA-DERIVED<br />
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NEUROBLASTOMA MYC ONCOGENE
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<strong><em>HGNC Approved Gene Symbol: MYCN</em></strong>
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<strong>SNOMEDCT:</strong> 702431004;
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Cytogenetic location: 2p24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:15,940,550-15,947,004 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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2p24.3
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Feingold syndrome 1
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164280
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Autosomal dominant
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3
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Megalencephaly-polydactyly syndrome
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620748
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The MYCN oncogene encodes a transcription factor belonging to the MYC (190080) family. It is primarily expressed in normal developing embryos and is thought to be critical in brain and other neural development. MYCN amplification is found in 20 to 30% of neuroblastoma tumors (see 256700), the most frequent extracranial solid tumors of childhood (summary by Wei et al., 2008). </p>
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<strong>Cloning and Expression</strong>
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<p>Kohl et al. (1983) isolated a genomic DNA segment homologous to the classic MYC oncogene that was amplified in neuroblastoma cell lines. They designated the gene corresponding to the DNA segment NMYC. </p><p>Michitsch and Melera (1985) cloned a partial NMYC cDNA from a neuroblastoma cell line. </p><p>Stanton et al. (1986) cloned a full-length NMYC cDNA. The deduced 456-amino acid protein has a calculated molecular mass of 49 kD. NMYC shares a high degree of similarity with MYC, particularly in the putative C-terminal DNA-binding domain. </p><p>Ramsay et al. (1986) identified 2 proteins originating from the same NMYC mRNA. Both were phosphorylated and exceptionally unstable. They were located in the cell nucleus and were bound to both single- and double-stranded DNA. </p><p>By sequencing several NMYC cDNA clones, Stanton and Bishop (1987) determined that transcription from the NMYC gene is complex. Transcription initiates at 2 clusters of sites that appear to be under the control of 2 distinct promoters. In addition, 2 alternative first exons, 1a and 1b, are spliced to a common acceptor site in exon 2. Both mRNAs encode the 65- and 67-kD NMYC proteins. However, exons 1a and 1b both contain putative short open reading frames, 2 of which are in favorable Kozak contexts. </p><p>By in situ hybridization and S1 nuclease protection analysis of early second-trimester human fetal tissues, Grady et al. (1987) found high NMYC RNA levels in cerebral germinal layer and primordial cortex and lower levels in the intermediate layer. After week 20, NMYC expression remained high in the undifferentiated outer cortex, but declined in the attenuated germinal layer and in the differentiating inner cortex. The primitive retina had high NMYC RNA levels in the inner nuclear and ganglion cell layers between 12 and 21 weeks. Lower levels of NMYC RNA were detected in some cells of lung and placenta. Grady et al. (1987) concluded that NMYC RNA is elevated in immature neural cells and disappears with differentiation. They speculated that NMYC upregulation may be unrelated to mitosis, since high levels occur in the primordial cortex, which grows by accretion and not by cell division. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<p>Stanton et al. (1986) determined that the MYCN gene is GC rich and contains 3 exons. Exon 1 is noncoding and contributes to a long 5-prime leader sequence. The 5-prime UTR contains 2 potential TATA boxes, the first of which probably denotes the major promoter. </p><p>Stanton and Bishop (1987) identified alternative first exons, 1a and 1b, in the MYCN gene that are spliced to the common exons 2 and 3. </p><p>Krystal et al. (1990) found that the GC-rich promoter of the MYCN gene functions as a bidirectional promoter to drive transcription of both the MYCN and NCYM genes in opposite directions. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>Kanda et al. (1983) used human-mouse hybrid cells to map NMYC to chromosome 2. In situ hybridization indicated that NMYC is on chromosome 2p. Schwab et al. (1984) assigned NMYC to chromosome 2p23 or 2p24. </p><p>Garson et al. (1987) used a novel in situ hybridization technique to map NMYC to chromosome 2p24. The nonradioactive technique combined the high spatial resolution and rapid signal development of the nonisotope approach with the previously unrivaled sensitivity of autoradiography. The method, which used biotin-labeled DNA probes and a streptavidin-alkaline phosphatase-based detection system, was compatible with G-banding and could be performed on archival material. </p><p>By study of mouse-hamster somatic cell hybrids, Campbell et al. (1989) mapped the mouse equivalent of NMYC to chromosome 12. By study of RFLPs in recombinant inbred strains, they mapped a second locus, called by them N-myc-2, to mouse chromosome 5. The locus on chromosome 5 may be a pseudogene. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<p><strong><em>Regulation of MYCN</em></strong></p><p>
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Manohar et al. (2002) identified at least 4 cis-acting destabilizing elements within the MYCN 3-prime UTR, and they found that HUD (ELAVL4; 168360) binding to this region stabilized MYCN mRNA in cells. Ectopic overexpression of HUD in mouse fibroblasts dramatically inhibited decay of a reporter RNA fused to either full-length MYCN 3-prime UTR or to cis-acting destabilizing elements harboring HUD-binding sites. Manohar et al. (2002) suggested that HUD may contribute to the malignant phenotype of neuroblastoma cells by stabilizing MYCN mRNA, thereby enhancing steady-state levels of expression of this oncogene. </p><p>By database analysis, Wei et al. (2008) found that 5 microRNA (miRNA) genes map to a region of chromosome 1p36 that is often deleted in neuroblastomas. Three of these miRNAs, MIR200B (612091), MIR429 (612094), and MIR34A (611172), were predicted to target the MYCN gene. Wei et al. (2008) found that transfection of MIR34A, but not MIR200B or MIR429, significantly reduced cell growth in IMR32 human fibroblasts and LAN5 human neuroblastoma cells, both of which overexpress MYCN. Western blot analysis showed that transfection of IMR32 and LAN5 cells with MIR34A significantly reduced MYCN expression. MIR34A also induced apoptosis in IMR32 cells. Reporter gene assays confirmed that MIR34A directly targeted the MYCN 3-prime UTR. RT-PCR revealed reduced MIR34A expression in 8 primary neuroblastomas with 1p36 deletion compared with those with normal copy number, and 7 of these showed MYCN overexpression. Wei et al. (2008) concluded that MIR34A suppresses MYCN expression and has a role in limiting cell growth. </p><p><strong><em>Antisense Transcription of MYCN</em></strong></p><p>
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Nuclear runoff transcription studies by Krystal et al. (1990) revealed sense and antisense transcription across exon 1 of the NMYC locus. They determined that both polyadenylated and nonpolyadenylated antisense transcripts (NCYM; 605374) are stable and that the nonpolyadenylated NCYM transcripts have 5-prime ends complementary to the 5-prime ends of the NMYC sense mRNA. Using a double RNase protection assay to analyze a human small cell lung cancer cell line, Krystal et al. (1990) found that most of the cytoplasmic nonpolyadenylated NCYM RNA existed in an RNA-RNA duplex with about 5% of the sense NMYC mRNA. Duplex formation appeared to occur with only a subset of the multiple forms of the NMYC mRNA, with the transcriptional initiation site of the sense NMYC RNA playing a role in determining this selectivity. Most duplexes included both exon 1 and intron 1 sequences of NMYC, and Krystal et al. (1990) hypothesized that duplex formation may modulate RNA processing by preserving a population of NMYC mRNA that retains intron 1. </p><p>Armstrong and Krystal (1992) cloned the NCYM gene, which overlaps with MYCN and is transcribed from the opposite DNA strand. The 2 genes appeared to be coregulated in tumor cell lines. </p><p><strong><em>Amplification and Overexpression of MYCN in Neuroblastomas</em></strong></p><p>
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Kohl et al. (1983) found that NMYC was amplified 25- to 700-fold in 8 of 9 human neuroblastoma (256700) cell lines that contained either homogeneous staining regions (HSR) or double minutes (DM), the karyologic manifestations of amplified genes. (The ninth cell line showed 30-fold amplification of the MYC oncogene.) Although NMYC is located on the short arm of chromosome 2, none of the 5 HSR-containing cell lines had HSRs on chromosome 2. Amplification of the NMYC gene also occurred in retinoblastoma. </p><p>Kohl et al. (1984) found amplified expression of NMYC in neuroblastoma cell lines, but not in other human tumor cell lines, with the exception of a retinoblastoma cell line. </p><p>Emanuel et al. (1985) and others have shown that neuroblastoma cell lines show HSRs at various sites, that the NMYC oncogene is amplified at several of these sites, and that there is apparently no preferred site for NMYC integration and amplification. Emanuel et al. (1985) stated that there was no direct evidence of amplification with HSR formation at 2p24-p23, the site of the NMYC gene. </p><p>Reviewing gene amplification in neuroblastomas, Brodeur and Seeger (1986) reported that they and other researchers had shown that most DM- and HSR-bearing neuroblastoma cell lines have multiple copies of NMYC. The amplification probably takes place at the level of the extrachromosomal DM, which appear to represent circular molecules, with subsequent linear integration into HSR. </p><p>Amplification of the MYCN gene is frequently seen either in extrachromosomal double minutes or in homogeneously staining regions in chromosomes of aggressively growing neuroblastomas. HSRs have never been observed at 2p24-p23, the map location of the MYCN gene. Corvi et al. (1994) used fluorescence in situ hybridization in the study of 5 human neuroblastoma cell lines to demonstrate that, in addition to amplified MYCN in HSRs or double minutes, single-copy MYCN was present at the normal position on chromosome 2. In 1 cell line there was coamplification of MYCN together with DNA of the host chromosome 12 to which MYCN had been transposed. The results suggested that the initial event is transposition of MYCN, with retention of the normal gene in its position on 2p before the occurrence of amplification. Thus, the mechanisms of amplified MYCN are probably different from those leading to amplification of drug-resistance genes. </p><p>Reiter and Brodeur (1996) generated a high-resolution restriction map of approximately 500 kb spanning the MYCN locus. They found that deletions and rearrangements of the amplicon occurred less often in primary tumors than in cell lines. They also defined a 130-kb common core region of the MYCN amplicon that was amplified in 32 of 33 neuroblastomas. The authors proposed that despite the large size of most MYCN amplicons, the core region that is consistently amplified in neuroblastomas probably contains the MYCN gene and little else. </p><p>Guo et al. (1999) performed a comprehensive analysis of deletions of 11q in neuroblastomas: 295 sporadic, 15 familial, and 21 tumor-derived cell lines. Loss of heterozygosity (LOH) analysis was performed at 24 microsatellite loci spanning 11q. LOH was observed at multiple 11q loci in 129 of 295 (44%) sporadic neuroblastomas, 5 of 15 (33%) familial neuroblastomas, and 5 of 21 (24%) neuroblastoma cell lines. A single region of 2.1 cM within 11q23.3, flanked by markers D11S1340 and D11S1299, was deleted in all specimens with 11q LOH. Allelic loss at 11q23 was inversely related to MYCN amplification (P less than 0.001). Within the subset of cases with a single copy of MYCN, 11q LOH was associated with advanced stage disease, unfavorable histopathology, and decreased overall survival probability. However, 11q LOH was not independently prognostic in multivariate analyses. These data were judged to support the hypothesis that a tumor suppressor gene mapping within 11q23.3 is commonly inactivated during the malignant evolution of a large subset of neuroblastomas, especially those with unamplified MYCN. </p><p>Molenaar et al. (2012) reported that LIN28B (611044) showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the LET7 (see 605386) miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-LET7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which Lin28b expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low Let7 miRNA levels and high Mycn protein expression. </p><p>Liu et al. (2014) identified a long noncoding RNA, lncUSMYCN (MYCNUT; 615968), upstream of the MYCN gene within the 130-kb region of chromosome 2 frequently amplified in neuroblastomas. They found that lncUSMYCN was coamplified with MYCN in a subset of primary neuroblastomas and neuroblastoma cell lines. Expression of lncUSMYCN was upregulated in only a few neuroblastomas that did not show MYCN amplification. Knockdown of lncUSMYCN via small interfering RNA reduced MYCN mRNA expression in a human neuroblastoma cell line, and ectopic expression of lncUSMYCN upregulated exogenous MYCN mRNA and induced cell proliferation. Unlike other lncRNAs, lncUSMYCN did not directly modulate MYCN promoter activity, but it bound directly to the RNA-binding protein NONO (300084), which then increased MYCN expression. High lncUSMYCN or NONO expression in neuroblastoma tissue independently predicted poor patient prognosis. Knockdown of lncUSMYCN reduced tumor growth in neuroblastoma-bearing mice. Liu et al. (2014) concluded that lncUSMYCN and NONO play important roles in regulating MYCN expression and neuroblastoma oncogenesis. </p><p>In MYCN-amplified neuroblastoma cell lines, Powers et al. (2016) showed that LIN28B is dispensable, despite derepression of LET7. Powers et al. (2016) demonstrated that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge LET7, which reconciles the dispensability of LIN28B. The authors found that genetic loss of LET7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. Powers et al. (2016) proposed that LET7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Finegold Syndrome 1</em></strong></p><p>
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Feingold syndrome-1 (FGLDS1; 164280) is an autosomal dominant disorder characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly, and cardiac defect. Van Bokhoven et al. (2005) carried out haplotype analysis in a previously unreported family with Feingold syndrome and confirmed linkage to the previously identified 7.3-cM locus on chromosome 2p24-p23 (Celli et al. (2000, 2003)). Affected members carried a microdeletion of maximally 1.2 Mb, encompassing MYCN but no other known or predicted gene, making it an excellent candidate for Feingold syndrome. In a cohort of 23 unrelated families with Feingold syndrome, van Bokhoven et al. (2005) sequenced the MYCN gene and identified 12 different heterozygous mutations in 15 families, 6 of which occurred de novo. Most mutations created stop codons or frameshifts in the 3-prime end of the open reading frame just before or in the regions encoding the basic helix-loop-helix and leucine-zipper domains. The authors identified 3 different missense mutations at 2 adjacent arginine residues (164840.0001-164840.0003). These arginines are at the core of the basic helix-loop-helix domain and are strictly conserved among members of the Myc family. The corresponding arginines in MYC (190080), arg366 and arg367, are crucial for DNA binding. Conservation of these residues suggests that they have a similar role in MYCN. Complete deletion of the MYCN gene was observed in 2 families, indicating that MYCN haploinsufficiency gives rise to a phenotype comparable to that observed for the other mutations and suggesting that these alleles are effectively null. </p><p>Marcelis et al. (2008) analyzed the MYCN gene in 93 patients from 50 families with a strong clinical suspicion of Feingold syndrome and identified 16 heterozygous mutations in 17 families with a total of 26 patients, including mutations in exon 2, which had not previously been reported (see, e.g., 164840.0007). The authors reviewed the clinical features of the 77 mutation-positive patients reported to date and compared them with the largest previous overview (Celli et al., 2003), noting that digital anomalies involving brachymesophalangy and toe syndactyly were the most consistent features, present in 100% and 97% of patients, respectively, whereas small head circumference was present in 89% of cases. Gastrointestinal atresia was the most important major congenital anomaly (55%), but renal and cardiac anomalies were also frequent (18% and 15%, respectively). Marcelis et al. (2008) suggested that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis. </p><p><strong><em>Megalencephaly-Polydactyly Syndrome</em></strong></p><p>
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In a patient with megalencephaly-polydactyly syndrome (MPAPA; 620748), Kato et al. (2019) identified a de novo heterozygous mutation in the MYCN gene (T58M; 164840.0008). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Expression of MYCN with the T58M mutation in HEK293 cells demonstrated that the protein was hypophosphorylated compared to wildtype. </p><p>In 2 patients with MPAPA, Nishio et al. (2023) identified de novo heterozygous missense mutations in the MYCN gene: the previously identified T58M mutation and P60L (164840.0009). Expression of MYCN with each mutation in HEK293 cells resulted in decreased phosphorylation at T58 compared to wildtype. MYCN with the T58M mutation was also more stable compared to wildtype. Both mutants were able to activate transcription of downstream genes. Nishio et al. (2023) concluded that T58M and P60L are gain-of-function mutations, which result in a mirror phenotype of Feingold syndrome-1 (164280), which results from loss-of-function mutations in MYCN. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nmyc is a downstream target of Shh (600725) signaling and promotes rapid cell division of granule neuron progenitors (GNPs) in mice. Nmyc overexpression can enforce proliferation of GNPs independently of Shh signaling, and conversely, its conditional loss during embryonic cerebellar development results in severe GNP deficiency, perturbs foliation, and leads to reduced cerebellar mass. Zindy et al. (2006) found that Myc mRNA levels increased in Nmyc-null mouse GNPs and that simultaneous deletion of both Myc and Nmyc exacerbated defective cerebellar development. Since Nmyc loss triggers precocious expression of the cyclin-dependent kinase inhibitors Kip1 (CDKN1B; 600778) and Ink4c (CDKN2C; 603369) in the cerebellar primordium, Zindy et al. (2006) disrupted Kip1 and Ink4c in Nmyc-null cerebella and found that this partially rescued GNP cell proliferation and cerebellar foliation. They concluded that expression of NMYC and concomitant downregulation of INK4C and KIP1 contribute to the proper development of the cerebellum. </p><p>Martins et al. (2008) found that mouse Nmyc was expressed in retinal progenitor cells, where it regulated proliferation in a cell-autonomous manner, and that it coordinated growth of the retina and eye. Retinas of Nmyc-deficient mice were hypocellular, but they were precisely proportioned to the size of the eye. Nmyc repressed expression of the cyclin-dependent kinase inhibitor p27(Kip1), but acted independently of cyclin D1 (168461). Acute inactivation of Nmyc led to increased expression of p27(Kip1), and simultaneous inactivation of p27(Kip1) and Nmyc rescued the hypocellular phenotype of Nmyc-deficient retinas. Nmyc was not required for retinal cell fate specification, differentiation, or survival. </p><p>Nishio et al. (2023) generated a mouse model with a heterozygous T58M mutation in the Mycn gene (T58M/WT) and a mouse model with a heterozygous frameshift mutation in exon 1 of the Mycn gene (FS/WT). The heterozygous T58M/WT mice had polydactyly and higher brain weights compared to FS/WT and WT mice, whereas FS/WT had lower brain weights than WT mice. Histologic examination of brains from the mutant mice showed that the T58M/WT mice had thicker cerebral cortex layers and FS/WT mice had thinner cerebral cortex layers at the primary motor cortex. Further studies suggested overproliferation of neural progenitors in the T58M/WT mice and underproliferation of neural progenitors in the FS/WT mice during early development. Additionally, T58M/WT had a variety of kidney abnormalities, including larger kidneys, unilateral kidny, and dilation of renal convoluted tubules, compared to WT and FS/WT mice. T58M/WT female mice were infertile and were found to have various uterovaginal malformations. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FEINGOLD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, ARG393HIS
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<br />
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SNP: rs104893646,
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ClinVar: RCV000014906, RCV001564807, RCV001849263
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 families with Feingold syndrome (FGLDS1; 164280), van Bokhoven et al. (2005) identified a heterozygous 1178G-A transition in the MYCN gene, resulting in an arg393-to-his (R393H) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 FEINGOLD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, ARG393SER
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<br />
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SNP: rs104893647,
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ClinVar: RCV000014907
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Feingold syndrome (FGLDS1; 164280), van Bokhoven et al. (2005) identified a heterozygous 1177C-A transversion in the MYCN gene, resulting in an arg393-to-ser (R393S) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FEINGOLD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, ARG394HIS
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<br />
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SNP: rs104893648,
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ClinVar: RCV000014908, RCV005089257
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Feingold syndrome (FGLDS1; 164280), van Bokhoven et al. (2005) identified a heterozygous 1181G-A transition in the MYCN gene, resulting in an arg394-to-his (R394H) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FEINGOLD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, GLU73TER
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<br />
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SNP: rs113994115,
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ClinVar: RCV000014910
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 4-year-old boy with Feingold syndrome (FGLDS1; 164280), Teszas et al. (2006) identified a heterozygous 217G-T transversion in exon 2 of the MYCN gene, resulting in a glu73-to-ter (E73X) substitution. The patient's mother and grandmother both carried the mutation and had less severe clinical anomalies including microcephaly and digital abnormalities with normal intelligence. Teszas et al. (2006) suggested that disorder in the mother and grandmother represents a milder form of Feingold syndrome. </p><p>In a proband with Feingold syndrome, Marcelis et al. (2008) identified compound heterozygosity for the E73X mutation and a 64C-T polymorphism, resulting in a gln22-to-ter (Q22X) substitution in exon 1 affecting only the N-terminally truncated 'delta-MYCN' isoform produced by initiation of translation in exon 1. The E73X mutation was found to segregate with disease in the mother and maternal grandmother, whereas the Q22X variant was found in the unaffected father, suggesting that variants involving only delta-MYCN do not contribute to Feingold syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 FEINGOLD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, 1-BP DUP, 626C
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<br />
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SNP: rs1558534266,
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ClinVar: RCV000014911, RCV003228894
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Turkish girl with Feingold syndrome (FGLDS1; 164280), Blaumeiser et al. (2008) identified a de novo heterozygous 1-bp duplication (626dupC) in exon 2 of the MYCN gene, predicted to result in premature termination and nonsense-mediated mRNA decay of the exon 2-3 transcript. Neither unaffected parent carried the mutation. The girl had dysmorphic facial features, developmental delay, and distal limb anomalies. Blaumeiser et al. (2008) noted that finding a mutation in exon 2 of the MYCN gene indicated that the MYCN transcript containing exon 2 is necessary for normal development. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 FEINGOLD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, ARG382HIS
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<br />
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SNP: rs121913666,
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ClinVar: RCV000014912, RCV004719647
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 5 affected members of a 3-generation family with Feingold syndrome (FGLDS1; 164280), Blaumeiser et al. (2008) identified a heterozygous 1145G-A transition in exon 3 of the MYCN gene, resulting in an arg382-to-his (R382H) substitution affecting a residue critical for DNA binding in the helix-loop-helix domain. There was wide phenotypic variability: 3 had mental retardation and finger and toe defects, of whom 1 also had intestinal atresia, whereas the other 2 showed only finger and toe anomalies. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 FEINGOLD SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, TRP77TER
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<br />
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SNP: rs121913667,
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ClinVar: RCV000014909
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with Feingold syndrome (FGLDS1; 164280), Marcelis et al. (2008) identified a heterozygous 231G-A transition in exon 2 of the MYCN gene, resulting in a trp77-to-ter (W77X) substitution that segregated with disease. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 MEGALENCEPHALY-POLYDACTYLY SYNDROME</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MYCN, THR58MET
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<br />
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ClinVar: RCV003234238, RCV003410288, RCV004721157
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 15-year-old boy with megalencephaly-polydactyly syndrome (MPAPA; 620748), who was negative for mutations in known megalencephaly genes, Kato et al. (2019) identified a de novo heterozygous c.173C-T transition (c.173C-T, NM_005378.5) in the MYCN gene, resulting in a thr58-to-met (T58M) substitution. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Expression of MYCN with the T58M mutation in HEK293 cells demonstrated that the protein was hypophosphorylated compared to wildtype. When MYCN with the T58M mutation was electroporated into mouse neuronal progenitor stem cells, the mutant Mycn was shown to be more stable and to induce higher levels of expression of Ccnd1 (168461) and Ccnd2 (123833) compared to wildtype Mycn. Kato et al. (2019) hypothesized that the T58M mutation resulted in a gain-of-function and stabilization of the MYCN protein. The increased accumulation of MYCN protein potentially prolonged expression of CCND1 and CCND2 and promoted neurogenesis in the developing cortex and thus megalencephaly. </p><p>In an 8-month-old Japanese boy (patient 2), born of nonconsanguineous parents, with MPAPA, Nishio et al. (2023) identified heterozygosity for the T58M mutation in the MYCN gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. MYCN with the T58M mutation was expressed in HEK293 cells and the level of phosphorylation at T58 was decreased compared to wildtype. MYCN with the T58M mutation was also more stable compared to wildtype. </p>
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<h4>
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<span class="mim-font">
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<strong>.0009 MEGALENCEPHALY-POLYDACTYLY SYNDROME</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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MYCN, PRO60LEU
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<br />
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ClinVar: RCV003154630, RCV003889282
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</span>
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<p>In a fetus (patient 1), conceived of nonconsanguineous French parents, with megalencephaly-polydactyly syndrome (MPAPA; 620748), Nishio et al. (2023) identified heterozygosity for a c.179C-T transition (c.179C-T, NM_005378.6) in the MYCN gene, resulting in a pro60-to-leu (P60L) substitution. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. The mutation was not present in the gnomAD database. MYCN with the P60L mutation was expressed in HEK293 cells and the level of phosphorylation at T58 was decreased compared to wildtype. MYCN with the P60L mutation was also more stable compared to wildtype. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Brodeur et al. (1984); Kohl et al. (1986); Lee et al. (1984); Schwab
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et al. (1983); Schwab et al. (1984); Schwab (1985); Seeger et al.
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(1985); Shiloh et al. (1985)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Molenaar, J. J., Domingo-Fernandez, R., Ebus, M. E., Lindner, S., Koster, J., Drabek, K., Mestdagh, P., van Sluis, P., Valentijn, L. J., van Nes, J., Broekmans, M., Haneveld, F., and 18 others.
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<strong>LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression.</strong>
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[PubMed: 23042116]
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<p class="mim-text-font">
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Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S.
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<strong>Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.</strong>
|
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Hum. Genet. Genomics Adv. 4: 100238, 2023.
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[PubMed: 37710961]
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[Full Text: https://doi.org/10.1016/j.xhgg.2023.100238]
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<p class="mim-text-font">
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