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Entry
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- *603856 - MAKORIN 3; MKRN3
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- OMIM
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<p>
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<span class="h4">*603856</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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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</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/603856">Table View</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 style="display: table-cell;">External Links</div>
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</a>
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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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=ENSG00000179455;t=ENST00000314520" 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=7681" 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=603856" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000179455;t=ENST00000314520" 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_005664" 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_005664" 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=603856" 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=04836&isoform_id=04836_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/MKRN3" 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/1001959,5032243,17368438,27881695,47123487,119578012" 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/Q13064" 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=7681" 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=ENSG00000179455;t=ENST00000314520" 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=MKRN3" 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=MKRN3" 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+7681" 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/MKRN3" 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:7681" 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/7681" 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=chr15&hgg_gene=ENST00000314520.6&hgg_start=23565674&hgg_end=23568044&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 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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</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:7114" 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/mkrn3" 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=603856[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=603856[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000179455" 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=MKRN3" 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=MKRN3" 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=MKRN3" 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=MKRN3&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/PA30833" 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:7114" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0029152.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2181178" 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/MKRN3#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:2181178" 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/7681/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://omia.org/OMIA002920/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7681" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002278;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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</div>
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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://reactome.org/content/query?q=MKRN3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603856
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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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MAKORIN 3; MKRN3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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ZINC FINGER PROTEIN 127; ZNF127; ZFP127
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MKRN3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MKRN3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/15/19?start=-3&limit=10&highlight=19">15q11.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:23565674-23568044&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'})">15:23,565,674-23,568,044</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/15/19?start=-3&limit=10&highlight=19">
|
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15q11.2
|
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</a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Precocious puberty, central, 2
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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|
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<a href="/entry/615346"> 615346 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603856" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603856" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#4" class="mim-tip-reference" title="Jong, M. T. C., Gray, T. A., Ji, Y., Glenn, C. C., Saitoh, S., Driscoll, D. J., Nicholls, R. D. <strong>A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.</strong> Hum. Molec. Genet. 8: 783-793, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196367</a>] [<a href="https://doi.org/10.1093/hmg/8.5.783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196367">Jong et al. (1999)</a> characterized 2 genes, termed ZNF127 (MKRN3) and ZNF127AS (<a href="/entry/603857">603857</a>), which are encoded in the complex imprinted locus on 15q11-q13. The ZNF127 gene encodes a 507-amino acid protein with a RING (C3HC4) zinc finger motif and multiple C3H zinc finger motifs, the former being closely related to a protein from variola major virus, the smallpox etiologic agent. These motifs predict ribonucleoprotein function for the ZNF127 polypeptide. Northern blot analysis revealed that the intronless ZNF127 gene is expressed ubiquitously as an approximately 3-kb transcript; however, the entire coding sequence and 5-prime CpG island overlap a second gene, ZNF127AS, which is transcribed from the antisense strand with a different transcript size and pattern of expression. Allele-specific analysis showed that the ZNF127 gene is expressed only from the paternal allele. Consistent with this expression pattern, in the brain, the ZNF127 5-prime CpG island is completely unmethylated on the paternal allele but methylated on the maternal allele. Analysis of adult testis, sperm, and fetal oocytes demonstrated a gametic methylation imprint with unmethylated paternal germ cells. Other work indicated that the ZNF127 gene is part of a coordinately regulated imprinted domain affected in Prader-Willi syndrome (PWS; <a href="/entry/176270">176270</a>) patients with imprinting mutations (<a href="#5" class="mim-tip-reference" title="Nicholls, R. D., Saitoh, S., Horsthemke, B. <strong>Imprinting in Prader-Willi and Angelman syndromes.</strong> Trends Genet. 14: 194-200, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9613204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9613204</a>] [<a href="https://doi.org/10.1016/s0168-9525(98)01432-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9613204">Nicholls et al., 1998</a>). Therefore, ZNF127 and ZNF127AS are novel imprinted genes that may be associated with some of the clinical features of the polygenic Prader-Willi syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10196367+9613204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Jong, M. T. C., Carey, A. H., Caldwell, K. A., Lau, M. H., Handel, M. A., Driscoll, D. J., Stewart, C. L., Rinchik, E. M., Nicholls, R. D. <strong>Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region.</strong> Hum. Molec. Genet. 8: 795-803, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196368</a>] [<a href="https://doi.org/10.1093/hmg/8.5.795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196368">Jong et al. (1999)</a> characterized the murine ZNF127 ortholog, termed Zfp127, which encodes a homologous putative zinc finger polypeptide. The mouse and human ZNF127 polypeptide sequences share similar structural motifs, including all 5 putative zinc finger motifs, and they have an overall identity of 69% at the amino acid level. Using RT-PCR across an in-frame hexamer tandem repeat and RNA from an interspecific F1 cross, <a href="#3" class="mim-tip-reference" title="Jong, M. T. C., Carey, A. H., Caldwell, K. A., Lau, M. H., Handel, M. A., Driscoll, D. J., Stewart, C. L., Rinchik, E. M., Nicholls, R. D. <strong>Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region.</strong> Hum. Molec. Genet. 8: 795-803, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196368</a>] [<a href="https://doi.org/10.1093/hmg/8.5.795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196368">Jong et al. (1999)</a> showed that the Zfp127 gene is expressed only from the paternal allele in brain, heart, and kidney. Similarly, Zfp127 was expressed in differentiated cells derived from androgenetic embryonic stem cells and normal embryos but not those from parthogenetic embryonic stem cells. <a href="#3" class="mim-tip-reference" title="Jong, M. T. C., Carey, A. H., Caldwell, K. A., Lau, M. H., Handel, M. A., Driscoll, D. J., Stewart, C. L., Rinchik, E. M., Nicholls, R. D. <strong>Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region.</strong> Hum. Molec. Genet. 8: 795-803, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196368</a>] [<a href="https://doi.org/10.1093/hmg/8.5.795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196368">Jong et al. (1999)</a> hypothesized that the gametic imprint may be set, at least in part, by the transcriptional activity of Zfp127 in pre- and postmeiotic male germ cells. They concluded that Zfp127 is a novel imprinted gene that may play a role in the imprinted phenotype of mouse models of PWS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The hypothalamic arcuate nucleus is the site of expression of several genes known to be important for puberty, including Kiss1 (<a href="/entry/603286">603286</a>) and Tac2 (TAC3; <a href="/entry/162330">162330</a>). <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> performed quantitative real-time PCR to assess Mkrn3 mRNA levels in the arcuate nucleus of mice, and observed in both male and female mice that levels were highest on postnatal days 10 and 12, began to decline on day 15, and reached a nadir by days 18 to 22, at which time Mkrn3 expression was 10 to 20% of the levels detected at 10 days. The timing of the decline in Mkrn3 expression correlated with the ages at which arcuate Kiss1 and Tac2 have been shown to increase, heralding the onset of puberty. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> performed whole-exome sequencing in 40 members of 15 families with central precocious puberty (CPPB2; <a href="/entry/615346">615346</a>) and identified heterozygosity for 3 frameshift mutations and 1 missense mutation in the MKRN3 gene (<a href="#0001">603856.0001</a>-<a href="#0004">603856.0004</a>) in affected individuals from 5 of the families. Sanger sequencing confirmed the mutations, and there was complete cosegregation with the phenotype in each of the families. All affected family members inherited their mutations from their fathers, consistent with a paternally expressed imprinted gene; the 1 heterozygous carrier known to have inherited his mutation from his mother was unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#6" class="mim-tip-reference" title="Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., and 192 others. <strong>Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.</strong> Nature 514: 92-97, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25231870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25231870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25231870[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/nature13545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25231870">Perry et al. (2014)</a> performed a metaanalysis using genomewide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, and found robust evidence (p less than 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with 3 loci (DLK1, <a href="/entry/176290">176290</a>-WDR25, <a href="/entry/618059">618059</a>; MKRN3-MAGEL2, <a href="/entry/605283">605283</a>; and KCNK9, <a href="/entry/605874">605874</a>) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. The significant paternal parent-of-origin effect in delaying age of menarche at the MKRN3-MAGEL2 locus was associated with SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12148769;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12148769</a> (p(pat) = 2.4 x 10(-6)). It was unclear which of the genes explained this menarche signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25231870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 14 (30%) of 46 probands with central precocious puberty, <a href="#7" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> identified heterozygous mutations in the MKRN3 gene (see, e.g., <a href="#0005">603856.0005</a>). A previously reported frameshift mutation (<a href="#0004">603856.0004</a>) was detected in 8 of the families, indicating a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L. <strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong> Horm. Res. Paediat. 88: 194-200, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28672280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28672280</a>] [<a href="https://doi.org/10.1159/000477441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28672280">Grandone et al. (2017)</a> analyzed the MKRN3 gene in 60 girls with central precocious puberty and identified 3 heterozygous mutations in 3 probands (see, e.g., <a href="#0005">603856.0005</a>), for an overall prevalence of 5%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28672280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs879255238 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255238;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=rs879255238" 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=rs879255238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 sibs with central precocious puberty (CPPB2; <a href="/entry/615346">615346</a>) and their unaffected father, <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> identified heterozygosity for a 1-bp deletion (c.637delC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Arg213GlyfsTer73) generating a truncated protein of 286 rather than 507 amino acids. The paternal grandmother, from whom DNA was not available, had a history of early menarche, suggesting that the unaffected father inherited the mutation from his mother but did not manifest the phenotype because only the paternally inherited MKRN3 allele is expressed. The mutation was not present in 3 other unaffected family members. The 2 sisters underwent thelarche at 5.75 and 6.5 years of age, and their brother had increased testicular volume at 8 years of age; all 3 sibs had pubertal levels of luteinizing hormone (LH; <a href="/entry/152780">152780</a>), both basal and stimulated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs879255239 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255239;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=rs879255239" 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=rs879255239" 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=RCV000050239" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000050239" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000050239</a>
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<p>In 2 Brazilian sisters with central precocious puberty (CPPB2; <a href="/entry/615346">615346</a>) and their affected father, paternal aunt, and paternal grandfather, <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> identified heterozygosity for a 1-bp insertion (c.1171_1172insA) in the MKRN3 gene, resulting in an immediate stop codon (Tyr391fsTer) that generates a protein of 391 amino acids rather than 507, lacking the last zinc finger motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs879255240 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255240;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs879255240?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879255240" 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=rs879255240" 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=RCV000050240" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000050240" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000050240</a>
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<p>In 3 affected sibs from a Belgian family with central precocious puberty (CPPB2; <a href="/entry/615346">615346</a>), <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> identified heterozygosity for a c.1095G-T transversion in the MKRN3 gene, resulting in an arg365-to-ser (R365S) substitution at a highly conserved residue in the RING-type zinc finger. The mutation was inherited from their unaffected father; their mother was wildtype for MKRN3, and both parents had a history of normal pubertal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0004 PRECOCIOUS PUBERTY, CENTRAL, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs763195944 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs763195944;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs763195944?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs763195944" 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=rs763195944" 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=RCV000050241 OR RCV001787846 OR RCV003415821" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000050241, RCV001787846, RCV003415821" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000050241...</a>
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<p>In 2 Brazilian brothers and a brother and sister from a family of European ancestry with central precocious puberty (CPPB2; <a href="/entry/615346">615346</a>), <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> identified heterozygosity for a 1-bp insertion (c.475_476insC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Ala162GlyfsTer14) and a truncated protein of 176 amino acids. Consistent with the pattern of a paternally expressed imprinted gene, in both families the mutation was inherited from an unaffected father, who likely inherited it from his mother. <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al. (2013)</a> stated that it was possible that the 2 families were distantly related. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 17 affected girls from 8 families with central precocious puberty, <a href="#7" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> identified heterozygosity for the previously reported 1-bp insertion in the MKRN3 gene, which these authors designated as c.482insC, resulting in a premature termination codon (Ala162GlyfsTer15). The mutation segregated with disease in the families and was found in each of 6 unaffected carrier fathers tested. Noting the high frequency of this mutation, <a href="#7" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> concluded that the cytosine homopolymer between nucleotides 476 and 482 is a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1264639964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1264639964;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1264639964?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1264639964" 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=rs1264639964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sisters and their unaffected father with central precocious puberty (CPPB2; <a href="/entry/615346">615346</a>), <a href="#7" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> identified heterozygosity for a c.982C-T transition in the MKRN3 gene, resulting in an arg328-to-cys (R328C) substitution. The mutation was not found in their unaffected mother or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 7-year-old girl with central precocious puberty, <a href="#2" class="mim-tip-reference" title="Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L. <strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong> Horm. Res. Paediat. 88: 194-200, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28672280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28672280</a>] [<a href="https://doi.org/10.1159/000477441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28672280">Grandone et al. (2017)</a> identified heterozygosity for the R328C mutation in the MKRN3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28672280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<p />
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<a id="1" class="mim-anchor"></a>
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<a id="Abreu2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others.
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<strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong>
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New Eng. J. Med. 368: 2467-2475, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[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=23738509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1302160" target="_blank">Full Text</a>]
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<a id="Grandone2017" class="mim-anchor"></a>
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Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L.
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<strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong>
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Horm. Res. Paediat. 88: 194-200, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28672280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28672280</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28672280" 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/10.1159/000477441" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="3" class="mim-anchor"></a>
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<a id="Jong1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Jong, M. T. C., Carey, A. H., Caldwell, K. A., Lau, M. H., Handel, M. A., Driscoll, D. J., Stewart, C. L., Rinchik, E. M., Nicholls, R. D.
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|
<strong>Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region.</strong>
|
|
Hum. Molec. Genet. 8: 795-803, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.5.795" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Jong1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Jong, M. T. C., Gray, T. A., Ji, Y., Glenn, C. C., Saitoh, S., Driscoll, D. J., Nicholls, R. D.
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<strong>A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.</strong>
|
|
Hum. Molec. Genet. 8: 783-793, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196367</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.5.783" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Nicholls1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nicholls, R. D., Saitoh, S., Horsthemke, B.
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<strong>Imprinting in Prader-Willi and Angelman syndromes.</strong>
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Trends Genet. 14: 194-200, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9613204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9613204</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9613204" 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/s0168-9525(98)01432-2" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Perry2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., and 192 others.
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<strong>Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.</strong>
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Nature 514: 92-97, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25231870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25231870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25231870[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=25231870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13545" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Simon2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N.
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<strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong>
|
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Europ. J. Endocr. 174: 1-8, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" 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/10.1530/EJE-15-0488" target="_blank">Full Text</a>]
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 09/07/2017
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/03/2014<br>Marla J. F. O'Neill - updated : 7/29/2013
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</span>
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</div>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/27/1999
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 07/24/2018
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/02/2017<br>carol : 09/07/2017<br>alopez : 12/03/2014<br>carol : 7/29/2013<br>carol : 7/29/2013<br>psherman : 10/22/1999<br>mgross : 10/21/1999<br>mgross : 5/27/1999
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603856
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<div>
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<h3>
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<span class="mim-font">
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MAKORIN 3; MKRN3
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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ZINC FINGER PROTEIN 127; ZNF127; ZFP127
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MKRN3</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 15q11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:23,565,674-23,568,044 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
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<span class="mim-font">
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15q11.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Precocious puberty, central, 2
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
615346
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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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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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</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>Jong et al. (1999) characterized 2 genes, termed ZNF127 (MKRN3) and ZNF127AS (603857), which are encoded in the complex imprinted locus on 15q11-q13. The ZNF127 gene encodes a 507-amino acid protein with a RING (C3HC4) zinc finger motif and multiple C3H zinc finger motifs, the former being closely related to a protein from variola major virus, the smallpox etiologic agent. These motifs predict ribonucleoprotein function for the ZNF127 polypeptide. Northern blot analysis revealed that the intronless ZNF127 gene is expressed ubiquitously as an approximately 3-kb transcript; however, the entire coding sequence and 5-prime CpG island overlap a second gene, ZNF127AS, which is transcribed from the antisense strand with a different transcript size and pattern of expression. Allele-specific analysis showed that the ZNF127 gene is expressed only from the paternal allele. Consistent with this expression pattern, in the brain, the ZNF127 5-prime CpG island is completely unmethylated on the paternal allele but methylated on the maternal allele. Analysis of adult testis, sperm, and fetal oocytes demonstrated a gametic methylation imprint with unmethylated paternal germ cells. Other work indicated that the ZNF127 gene is part of a coordinately regulated imprinted domain affected in Prader-Willi syndrome (PWS; 176270) patients with imprinting mutations (Nicholls et al., 1998). Therefore, ZNF127 and ZNF127AS are novel imprinted genes that may be associated with some of the clinical features of the polygenic Prader-Willi syndrome. </p><p>Jong et al. (1999) characterized the murine ZNF127 ortholog, termed Zfp127, which encodes a homologous putative zinc finger polypeptide. The mouse and human ZNF127 polypeptide sequences share similar structural motifs, including all 5 putative zinc finger motifs, and they have an overall identity of 69% at the amino acid level. Using RT-PCR across an in-frame hexamer tandem repeat and RNA from an interspecific F1 cross, Jong et al. (1999) showed that the Zfp127 gene is expressed only from the paternal allele in brain, heart, and kidney. Similarly, Zfp127 was expressed in differentiated cells derived from androgenetic embryonic stem cells and normal embryos but not those from parthogenetic embryonic stem cells. Jong et al. (1999) hypothesized that the gametic imprint may be set, at least in part, by the transcriptional activity of Zfp127 in pre- and postmeiotic male germ cells. They concluded that Zfp127 is a novel imprinted gene that may play a role in the imprinted phenotype of mouse models of PWS. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The hypothalamic arcuate nucleus is the site of expression of several genes known to be important for puberty, including Kiss1 (603286) and Tac2 (TAC3; 162330). Abreu et al. (2013) performed quantitative real-time PCR to assess Mkrn3 mRNA levels in the arcuate nucleus of mice, and observed in both male and female mice that levels were highest on postnatal days 10 and 12, began to decline on day 15, and reached a nadir by days 18 to 22, at which time Mkrn3 expression was 10 to 20% of the levels detected at 10 days. The timing of the decline in Mkrn3 expression correlated with the ages at which arcuate Kiss1 and Tac2 have been shown to increase, heralding the onset of puberty. </p>
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</span>
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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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<span class="mim-text-font">
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<p>Abreu et al. (2013) performed whole-exome sequencing in 40 members of 15 families with central precocious puberty (CPPB2; 615346) and identified heterozygosity for 3 frameshift mutations and 1 missense mutation in the MKRN3 gene (603856.0001-603856.0004) in affected individuals from 5 of the families. Sanger sequencing confirmed the mutations, and there was complete cosegregation with the phenotype in each of the families. All affected family members inherited their mutations from their fathers, consistent with a paternally expressed imprinted gene; the 1 heterozygous carrier known to have inherited his mutation from his mother was unaffected. </p><p>Perry et al. (2014) performed a metaanalysis using genomewide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, and found robust evidence (p less than 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with 3 loci (DLK1, 176290-WDR25, 618059; MKRN3-MAGEL2, 605283; and KCNK9, 605874) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. The significant paternal parent-of-origin effect in delaying age of menarche at the MKRN3-MAGEL2 locus was associated with SNP rs12148769 (p(pat) = 2.4 x 10(-6)). It was unclear which of the genes explained this menarche signal. </p><p>In 14 (30%) of 46 probands with central precocious puberty, Simon et al. (2016) identified heterozygous mutations in the MKRN3 gene (see, e.g., 603856.0005). A previously reported frameshift mutation (603856.0004) was detected in 8 of the families, indicating a mutation hotspot. </p><p>Grandone et al. (2017) analyzed the MKRN3 gene in 60 girls with central precocious puberty and identified 3 heterozygous mutations in 3 probands (see, e.g., 603856.0005), for an overall prevalence of 5%. </p>
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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>5 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 PRECOCIOUS PUBERTY, CENTRAL, 2</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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MKRN3, 1-BP DEL, 637C
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<br />
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SNP: rs879255238,
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ClinVar: RCV000050238
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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 3 sibs with central precocious puberty (CPPB2; 615346) and their unaffected father, Abreu et al. (2013) identified heterozygosity for a 1-bp deletion (c.637delC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Arg213GlyfsTer73) generating a truncated protein of 286 rather than 507 amino acids. The paternal grandmother, from whom DNA was not available, had a history of early menarche, suggesting that the unaffected father inherited the mutation from his mother but did not manifest the phenotype because only the paternally inherited MKRN3 allele is expressed. The mutation was not present in 3 other unaffected family members. The 2 sisters underwent thelarche at 5.75 and 6.5 years of age, and their brother had increased testicular volume at 8 years of age; all 3 sibs had pubertal levels of luteinizing hormone (LH; 152780), both basal and stimulated. </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 PRECOCIOUS PUBERTY, CENTRAL, 2</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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MKRN3, 1-BP INS, 1171A
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<br />
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SNP: rs879255239,
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ClinVar: RCV000050239
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Brazilian sisters with central precocious puberty (CPPB2; 615346) and their affected father, paternal aunt, and paternal grandfather, Abreu et al. (2013) identified heterozygosity for a 1-bp insertion (c.1171_1172insA) in the MKRN3 gene, resulting in an immediate stop codon (Tyr391fsTer) that generates a protein of 391 amino acids rather than 507, lacking the last zinc finger motif. </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 PRECOCIOUS PUBERTY, CENTRAL, 2</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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MKRN3, ARG365SER
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<br />
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SNP: rs879255240,
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gnomAD: rs879255240,
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ClinVar: RCV000050240
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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 3 affected sibs from a Belgian family with central precocious puberty (CPPB2; 615346), Abreu et al. (2013) identified heterozygosity for a c.1095G-T transversion in the MKRN3 gene, resulting in an arg365-to-ser (R365S) substitution at a highly conserved residue in the RING-type zinc finger. The mutation was inherited from their unaffected father; their mother was wildtype for MKRN3, and both parents had a history of normal pubertal 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>.0004 PRECOCIOUS PUBERTY, CENTRAL, 2</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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MKRN3, 1-BP INS, 475C
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<br />
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SNP: rs763195944,
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gnomAD: rs763195944,
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ClinVar: RCV000050241, RCV001787846, RCV003415821
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Brazilian brothers and a brother and sister from a family of European ancestry with central precocious puberty (CPPB2; 615346), Abreu et al. (2013) identified heterozygosity for a 1-bp insertion (c.475_476insC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Ala162GlyfsTer14) and a truncated protein of 176 amino acids. Consistent with the pattern of a paternally expressed imprinted gene, in both families the mutation was inherited from an unaffected father, who likely inherited it from his mother. Abreu et al. (2013) stated that it was possible that the 2 families were distantly related. </p><p>In 17 affected girls from 8 families with central precocious puberty, Simon et al. (2016) identified heterozygosity for the previously reported 1-bp insertion in the MKRN3 gene, which these authors designated as c.482insC, resulting in a premature termination codon (Ala162GlyfsTer15). The mutation segregated with disease in the families and was found in each of 6 unaffected carrier fathers tested. Noting the high frequency of this mutation, Simon et al. (2016) concluded that the cytosine homopolymer between nucleotides 476 and 482 is a mutation hotspot. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 PRECOCIOUS PUBERTY, CENTRAL, 2</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MKRN3, ARG328CYS
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<br />
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SNP: rs1264639964,
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gnomAD: rs1264639964,
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ClinVar: RCV000505267
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 sisters and their unaffected father with central precocious puberty (CPPB2; 615346), Simon et al. (2016) identified heterozygosity for a c.982C-T transition in the MKRN3 gene, resulting in an arg328-to-cys (R328C) substitution. The mutation was not found in their unaffected mother or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. </p><p>In a 7-year-old girl with central precocious puberty, Grandone et al. (2017) identified heterozygosity for the R328C mutation in the MKRN3 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others.
|
|
<strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong>
|
|
New Eng. J. Med. 368: 2467-2475, 2013.
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[PubMed: 23738509]
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[Full Text: https://doi.org/10.1056/NEJMoa1302160]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L.
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<strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong>
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Horm. Res. Paediat. 88: 194-200, 2017.
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[PubMed: 28672280]
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[Full Text: https://doi.org/10.1159/000477441]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jong, M. T. C., Carey, A. H., Caldwell, K. A., Lau, M. H., Handel, M. A., Driscoll, D. J., Stewart, C. L., Rinchik, E. M., Nicholls, R. D.
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|
<strong>Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region.</strong>
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Hum. Molec. Genet. 8: 795-803, 1999.
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[PubMed: 10196368]
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[Full Text: https://doi.org/10.1093/hmg/8.5.795]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jong, M. T. C., Gray, T. A., Ji, Y., Glenn, C. C., Saitoh, S., Driscoll, D. J., Nicholls, R. D.
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<strong>A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.</strong>
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Hum. Molec. Genet. 8: 783-793, 1999.
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[PubMed: 10196367]
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[Full Text: https://doi.org/10.1093/hmg/8.5.783]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Nicholls, R. D., Saitoh, S., Horsthemke, B.
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<strong>Imprinting in Prader-Willi and Angelman syndromes.</strong>
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Trends Genet. 14: 194-200, 1998.
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[PubMed: 9613204]
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[Full Text: https://doi.org/10.1016/s0168-9525(98)01432-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., and 192 others.
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<strong>Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.</strong>
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Nature 514: 92-97, 2014.
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[PubMed: 25231870]
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[Full Text: https://doi.org/10.1038/nature13545]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N.
|
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<strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong>
|
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Europ. J. Endocr. 174: 1-8, 2016.
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[PubMed: 26431553]
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[Full Text: https://doi.org/10.1530/EJE-15-0488]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 09/07/2017<br>Ada Hamosh - updated : 12/03/2014<br>Marla J. F. O'Neill - updated : 7/29/2013
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/27/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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mgross : 07/24/2018<br>carol : 10/02/2017<br>carol : 09/07/2017<br>alopez : 12/03/2014<br>carol : 7/29/2013<br>carol : 7/29/2013<br>psherman : 10/22/1999<br>mgross : 10/21/1999<br>mgross : 5/27/1999
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