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Entry
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- *613733 - MENIN 1 ; MEN1
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- OMIM
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<p>
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<span class="h4">*613733</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/613733">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000133895;t=ENST00000450708" 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=4221" 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=613733" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000133895;t=ENST00000450708" 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_000244,NM_001370251,NM_001370259,NM_001370260,NM_001370261,NM_001370262,NM_001370263,NM_001407142,NM_001407143,NM_001407144,NM_001407145,NM_001407146,NM_001407147,NM_001407148,NM_001407149,NM_001407150,NM_001407151,NM_001407152,NM_130799,NM_130800,NM_130801,NM_130802,NM_130803,NM_130804,NR_176284,NR_176285,NR_176286,NR_176287,XM_017017766,XM_017017767,XM_017017768" 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_001370259" 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=613733" 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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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/MEN1" 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/1945387,1945389,1945390,2217972,10944927,10944929,10944931,10944933,10944935,12803441,31747029,32250735,38197214,119594709,119594710,119594711,119594712,119594713,119594714,119594715,119594716,119594717,119594718,119594719,119594720,119594721,146230099,146230101,146230103,146230105,146230107,146230109,146230111,257450058,363399262,1034573758,1034573760,1034573762,1779948667,2199215476,2199215488,2199215493,2199215529,2199215535,2199215550,2199215559,2199215565,2199215567,2199215573,2199215575,2199215577,2245367869,2245367873,2245367877,2245367879,2245367890,2245367921,2245367927,2245367975,2245367981,2245368006,2245368018,2462525300,2462525302,2619680071" 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/O00255" 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 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=4221" 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=ENSG00000133895;t=ENST00000450708" 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=MEN1" 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=MEN1" 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+4221" 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/MEN1" 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:4221" 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/4221" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr11&hgg_gene=ENST00000450708.7&hgg_start=64803516&hgg_end=64811294&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7010" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7010" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/men1" 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=613733[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=613733[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/ENSG00000133895" 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=MEN1" 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=MEN1" 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=MEN1" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www.arup.utah.edu/database/MEN1/MEN1_welcome.php" title="Multiple endocrine neoplasia and MEN1 missense variants Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Multiple endocrine neoplas…</a></div><div style="margin-left: 0.5em;"><a href="http://www.umd.be/MEN1/" title="The UMD MEN1 mutations database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">The UMD MEN1 mutations dat…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MEN1&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/PA30746" 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:7010" 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/FBgn0031885.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:1316736" 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/MEN1#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:1316736" 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/4221/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4221" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-991110-12" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4221" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=MEN1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 254627002, 30664006, 786037006<br />
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<strong>ICD10CM:</strong> E31.21<br />
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<strong>ICD9CM:</strong> 258.01<br />
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">ICD+</a>
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</div>
|
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
613733
|
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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>
|
|
<span class="mim-font">
|
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MENIN 1 ; MEN1
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</span>
|
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</h3>
|
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</div>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MEN1 GENE<br />
|
|
MENIN
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MEN1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MEN1</a></em></strong>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/561?start=-3&limit=10&highlight=561">11q13.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:64803516-64811294&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">11:64,803,516-64,811,294</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=131100," class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="6">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/561?start=-3&limit=10&highlight=561">
|
|
11q13.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Adrenal adenoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The MEN1 gene encodes menin, a nuclear scaffold protein that regulates gene transcription by coordinating chromatin remodeling. Menin interacts with several transcription factors, including JUND (<a href="/entry/165162">165162</a>), NFKB (<a href="/entry/164011">164011</a>), and SMAD3 (<a href="/entry/603109">603109</a>). MEN1 is considered to act as a tumor suppressor gene (summary by <a href="#9" class="mim-tip-reference" title="Canaff, L., Vanbellinghen, J.-F., Kaji, H., Goltzman, D., Hendy, G. N. <strong>Impaired transforming growth factor-beta (TGF-beta) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).</strong> J. Biol. Chem. 287: 8584-8597, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22275377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22275377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22275377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.341958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22275377">Canaff et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22275377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified several candidate genes within the multiple endocrine neoplasia type I (MEN1; <a href="/entry/131100">131100</a>) minimal interval on chromosome 11q13. One of the genes (MEN1) was found to encode a deduced 610-amino acid protein, which the authors designated menin. Northern blot analysis revealed ubiquitous expression of a 2.8-kb MEN1 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify additional candidate genes in the segment of less than 300 kb where the MEN1 locus is situated, <a href="#34" class="mim-tip-reference" title="Lemmens, I., Van de Ven, W. J. M., Kas, K., Zhang, C. X., Giraud, S., Wautot, V., Buisson, N., De Witte, K., Salandre, J., Lenoir, G., Pugeat, M., Calender, A., and 19 others. <strong>Identification of the multiple endocrine neoplasia type 1 (MEN1) gene.</strong> Hum. Molec. Genet. 6: 1177-1183, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9215690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9215690</a>] [<a href="https://doi.org/10.1093/hmg/6.7.1177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9215690">Lemmens et al. (1997)</a> used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes they identified, which they called SCG2 (suppressor candidate gene-2), proved to be identical to the MEN1 gene reported by <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a>. The SCG2 transcript was 2.9 kb in all tissues studied, with an additional 4.2-kb transcript also being present in the pancreas and thymus. A human SCG2 cDNA clone, covering 2.3 kb at the 3-prime end of the gene, was isolated by hybridization screening. Northern blot analysis with this human sequence gave results identical to those from the bovine sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9103196+9215690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> determined that the MEN1 gene contains 10 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified the MEN1 gene on chromosome 11q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" 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>Based on immunofluorescence, Western blotting of subcellular fractions, and epitope tagging with enhanced green fluorescent protein, <a href="#27" class="mim-tip-reference" title="Guru, S. C., Goldsmith, P. K., Burns, A. L., Marx, S. J., Spiegel, A. M., Collins, F. S., Chandrasekharappa, S. C. <strong>Menin, the product of the MEN1 gene, is a nuclear protein.</strong> Proc. Nat. Acad. Sci. 95: 1630-1634, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465067</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9465067[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.4.1630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465067">Guru et al. (1998)</a> demonstrated that menin is located primarily in the nucleus. They identified at least 2 independent nuclear localizations signals (NLSs), both located in the C-terminal fourth of the protein. They pointed out that among the 68 then-known independent disease-associated mutations, none of the 22 missense and 3 in-frame deletions affected either of the putative NLS sequences. However, if expressed, none of the truncated menin proteins resulting from the 43 known frameshift/nonsense mutations would retain both the NLSs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9465067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a yeast 2-hybrid screen with menin as the bait, <a href="#1" class="mim-tip-reference" title="Agarwal, S. K., Guru, S. C., Heppner, C., Erdos, M. R., Collins, R. M., Park, S. Y., Saggar, S., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Marx, S. J., Burns, A. L. <strong>Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.</strong> Cell 96: 143-152, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989505</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80967-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989505">Agarwal et al. (1999)</a> identified the transcription factor JunD (<a href="/entry/165162">165162</a>) as a direct menin-interacting partner. Menin did not interact directly with other Jun and Fos family members. The menin-JunD interaction was confirmed in vitro and in vivo. Menin repressed transcriptional activation mediated by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive reporter, or by JunD from an AP1-responsive reporter. Several naturally occurring and clustered MEN1 missense mutations disrupted menin interaction with JunD. These observations suggest that the tumor suppressor function of menin involves direct binding to JunD and inhibition of JunD-activated transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9989505" 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="#32" class="mim-tip-reference" title="Kaji, H., Canaff, L., Lebrun, J.-J., Goltzman, D., Hendy, G. N. <strong>Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling.</strong> Proc. Nat. Acad. Sci. 98: 3837-3842, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11274402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11274402</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11274402[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.061358098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11274402">Kaji et al. (2001)</a> showed that menin inactivation by antisense RNA antagonizes transforming growth factor-beta (TGFB; <a href="/entry/190180">190180</a>)-mediated cell growth inhibition. Menin interacts with SMAD3 (<a href="/entry/603109">603109</a>), and antisense menin suppresses TGFB-induced and SMAD3-induced transcriptional activity by inhibiting SMAD3/4-DNA binding at specific transcriptional regulatory sites. These results implicated a mechanism of tumorigenesis by menin inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11274402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate how menin expression is regulated in both man and mouse, <a href="#52" class="mim-tip-reference" title="Zablewska, B., Bylund, L., Mandic, S. A., Fromaget, M., Gaudray, P., Weber, G. <strong>Transcription regulation of the multiple endocrine neoplasia type 1 gene in human and mouse.</strong> J. Clin. Endocr. Metab. 88: 3845-3851, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915678</a>] [<a href="https://doi.org/10.1210/jc.2003-030288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915678">Zablewska et al. (2003)</a> assayed a greater than 1 kb region upstream of the second exon of the MEN1 gene for promoter activity in luciferase reporter vectors. The basic promoter was located closely upstream of the most commonly expressed first exon. The region further upstream modified the activity. Repetitive elements of the short interspersed/Alu type covered the entire human upstream regulatory region and were the only apparent motif in common with its murine ortholog. They found that overexpression of menin in an inducible cell culture system downregulated the proximal promoter. In response to downregulation of MEN1 expression by RNA interference, the regulatory region activated the promoter in a compensatory manner. They concluded that their data confirmed that the expression of the MEN1 gene is regulated by feedback from its product menin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To explore telomerase regulation, <a href="#36" class="mim-tip-reference" title="Lin, S.-Y., Elledge, S. J. <strong>Multiple tumor suppressor pathways negatively regulate telomerase.</strong> Cell 113: 881-889, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12837246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12837246</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00430-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12837246">Lin and Elledge (2003)</a> employed a general genetic screen in HeLa cells to identify negative regulators of TERT (<a href="/entry/187270">187270</a>). They discovered 3 tumor suppressor/oncogene pathways involved in TERT repression, including menin, which is a direct repressor of TERT. Depleting menin immortalized primary human fibroblasts and caused a transformation phenotype when coupled with expression of simian virus 40 large and small T antigen and oncogenic RAS (<a href="/entry/190020">190020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12837246" 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>Human ML-2 leukemia cells lack a normal MLL (<a href="/entry/159555">159555</a>) gene and exclusively express an MLL/AF6 (MLLT4; <a href="/entry/159559">159559</a>) fusion protein. <a href="#51" class="mim-tip-reference" title="Yokoyama, A., Somervaille, T. C. P., Smith, K. S., Rozenblatt-Rosen, O., Meyerson, M., Cleary, M. L. <strong>The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.</strong> Cell 123: 207-218, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239140</a>] [<a href="https://doi.org/10.1016/j.cell.2005.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239140">Yokoyama et al. (2005)</a> showed that MLL/AF6 associated with menin (MEN1) in ML-2 cells. Chromatin immunoprecipitation analysis showed both proteins present on upstream sites of the HOXA7 (<a href="/entry/142950">142950</a>), HOXA9 (<a href="/entry/142956">142956</a>), and HOXA10 (<a href="/entry/142957">142957</a>) promoters. Deletions and point mutations performed in the MLL portion of the MLL/ENL (MLLT1; <a href="/entry/159556">159556</a>) fusion protein revealed a high affinity menin-binding motif (RXRFP) near the N-terminus. Interaction between oncogenic MLL and menin was required for initiation of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin was essential to maintain MLL-associated myeloid transformation. Acute genetic ablation of menin in mice reversed aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes and specifically abrogated differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#30" class="mim-tip-reference" title="Huang, J., Gurung, B., Wan, B., Matkar, S., Veniaminova, N. A., Wan, K., Merchant, J. L., Hua, X., Lei, M. <strong>The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.</strong> Nature 482: 542-546, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22327296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22327296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22327296[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/nature10806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22327296">Huang et al. (2012)</a> reported the crystal structures of human menin in its free form and in complexes with MLL1 (<a href="/entry/159555">159555</a>) or with JUND (<a href="/entry/165162">165162</a>), or with an MLL1-LEDGF (<a href="/entry/603620">603620</a>) heterodimer. These structures showed that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22327296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified mutations in the MEN1 gene (<a href="#0001">613733.0001</a>-<a href="#0012">613733.0012</a>) in 14 probands from 15 families with multiple endocrine neoplasia type I. Twelve different heterozygous mutations were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By mutation analysis of the SCG2 in 10 unrelated families with multiple endocrine neoplasia type I, <a href="#34" class="mim-tip-reference" title="Lemmens, I., Van de Ven, W. J. M., Kas, K., Zhang, C. X., Giraud, S., Wautot, V., Buisson, N., De Witte, K., Salandre, J., Lenoir, G., Pugeat, M., Calender, A., and 19 others. <strong>Identification of the multiple endocrine neoplasia type 1 (MEN1) gene.</strong> Hum. Molec. Genet. 6: 1177-1183, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9215690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9215690</a>] [<a href="https://doi.org/10.1093/hmg/6.7.1177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9215690">Lemmens et al. (1997)</a> identified 1 polymorphism and 9 different heterozygous mutations (1 missense, 4 nonsense, 1 insertional, and 3 deletional frameshifts) that segregated with the disease, thus providing confirmation for the identification of the MEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9215690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Giraud, S., Zhang, C. X., Serova-Sinilnikova, O., Wautot, V., Salandre, J., Buisson, N., Waterlot, C., Bauters, C., Porchet, N., Aubert, J.-P., Emy, P., Cadiot, G., and 29 others. <strong>Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.</strong> Am. J. Hum. Genet. 63: 455-467, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683585</a>] [<a href="https://doi.org/10.1086/301953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683585">Giraud et al. (1998)</a> studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683585" 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="#47" class="mim-tip-reference" title="Teh, B. T., Kytola, S., Farnebo, F., Bergman, L., Wong, F. K., Weber, G., Hayward, N., Larsson, C., Skogseid, B., Beckers, A., Phelan, C., Edwards, M., and 29 others. <strong>Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.</strong> J. Clin. Endocr. Metab. 83: 2621-2626, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9709921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9709921</a>] [<a href="https://doi.org/10.1210/jcem.83.8.5059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9709921">Teh et al. (1998)</a> performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (<a href="#0032">613733.0032</a>) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709921" 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 Spain, <a href="#12" class="mim-tip-reference" title="Cebrian, A., Herrera-Pombo, J. L., Diez, J. J., Sanchez-Vilar, O., Lara, J. I., Vazquez, C., Pico, A., Osorio, A., Martinez-Delgado, B., Benitez, J., Robledo, M. <strong>Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1.</strong> Europ. J. Hum. Genet. 7: 585-589, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10439966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10439966</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10439966">Cebrian et al. (1999)</a> studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10439966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The observation of loss of heterozygosity involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. <a href="#39" class="mim-tip-reference" title="Pannett, A. A. J., Thakker, R. V. <strong>Somatic mutations in MEN type 1 tumors, consistent with the Knudson 'two-hit' hypothesis.</strong> J. Clin. Endocr. Metab. 86: 4371-4374, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549677</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549677">Pannett and Thakker (2001)</a> searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, <a href="#50" class="mim-tip-reference" title="Wautot, V., Vercherat, C., Lespinasse, J., Chambe, B., Lenoir, G. M., Zhang, C. X., Porchet, N., Cordier, M., Beroud, C., Calender, A. <strong>Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein.</strong> Hum. Mutat. 20: 35-47, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112656</a>] [<a href="https://doi.org/10.1002/humu.10092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112656">Wautot et al. (2002)</a> identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (<a href="/entry/165162">165162</a>), SMAD3, and nuclear factor kappa-B (NFKB1; <a href="/entry/164011">164011</a>), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (<a href="#0024">613733.0024</a>). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (<a href="#0025">613733.0025</a>), 209-211 (<a href="#0026">613733.0026</a>), 418 (<a href="#0027">613733.0027</a>), and 516 (<a href="#0028">613733.0028</a>) accounts for 36.6% of all mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" 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 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, <a href="#37" class="mim-tip-reference" title="Okamoto, H., Tamada, A., Hai, N., Doi, M., Uchimura, I., Hirata, Y., Kosugi, S. <strong>A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism.</strong> Jpn. J. Clin. Oncol. 32: 368-370, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417605</a>] [<a href="https://doi.org/10.1093/jjco/hyf079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417605">Okamoto et al. (2002)</a> identified a heterozygous germline mutation in exon 4 of the MEN1 gene (<a href="#0030">613733.0030</a>). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417605" 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="#40" class="mim-tip-reference" title="Park, J.-H., Kim, I.-J., Kang, H. C., Lee, S.-H., Shin, Y., Kim, K.-H., Lim, S.-B., Kang, S.-B., Lee, K. U., Kim, S. Y., Lee, M.-S., Lee, M.-K., Park, J.-H., Moon, S.-D., Park, J.-G. <strong>Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders.</strong> Clin. Genet. 64: 48-53, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791038</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00091.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791038">Park et al. (2003)</a> investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Isolated Primary Hyperparathyroidism, MEN1 Variant</em></strong></p><p>
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In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism, <a href="#46" class="mim-tip-reference" title="Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E. <strong>A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)</strong> Am. J. Hum. Genet. 63: 1544-1549, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792884</a>] [<a href="https://doi.org/10.1086/302097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792884">Teh et al. (1998)</a> found that affected members had a germline missense mutation in the MEN1 gene (<a href="#0020">613733.0020</a>). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1 (<a href="/entry/131100">131100</a>). The pattern of transmission was autosomal dominant with high penetrance, as in MEN1. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, <a href="#46" class="mim-tip-reference" title="Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E. <strong>A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)</strong> Am. J. Hum. Genet. 63: 1544-1549, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792884</a>] [<a href="https://doi.org/10.1086/302097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792884">Teh et al. (1998)</a> demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792884" 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 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas, <a href="#22" class="mim-tip-reference" title="Fujimori, M., Shirahama, S., Sakurai, A., Hashizume, K., Hama, Y., Ito, K., Shingu, K., Kobayashi, S., Amano, J., Fukushima, Y. <strong>Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism.</strong> Am. J. Med. Genet. 80: 221-222, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843042</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19981116)80:3<221::aid-ajmg8>3.0.co;2-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843042">Fujimori et al. (1998)</a> identified a missense mutation in the MEN1 gene (<a href="#0021">613733.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations in the MEN1 Gene</em></strong></p><p>
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<a href="#28" class="mim-tip-reference" title="Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., Emmert-Buck, M. R., Guru, S. C., Manickam, P., Olufemi, S.-E., Skarulis, M. C., Doppman, J. L., Alexander, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Somatic mutation of the MEN1 gene in parathyroid tumours.</strong> Nature Genet. 16: 375-378, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241276</a>] [<a href="https://doi.org/10.1038/ng0897-375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241276">Heppner et al. (1997)</a> found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (<a href="#0013">613733.0013</a>) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). <a href="#28" class="mim-tip-reference" title="Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., Emmert-Buck, M. R., Guru, S. C., Manickam, P., Olufemi, S.-E., Skarulis, M. C., Doppman, J. L., Alexander, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Somatic mutation of the MEN1 gene in parathyroid tumours.</strong> Nature Genet. 16: 375-378, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241276</a>] [<a href="https://doi.org/10.1038/ng0897-375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241276">Heppner et al. (1997)</a> suggested that many of these tumors likewise may have MEN1 somatic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Carling, T., Correa, P., Hessman, O., Hedberg, J., Skogseid, B., Lindberg, D., Rastad, J., Westin, G., Akerstrom, G. <strong>Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism.</strong> J. Clin. Endocr. Metab. 83: 2960-2963, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9709976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9709976</a>] [<a href="https://doi.org/10.1210/jcem.83.8.4977" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9709976">Carling et al. (1998)</a> used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (<a href="/entry/168450">168450</a>) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Farnebo, F., Teh, B. T., Kytola, S., Svensson, A., Phelan, C., Sandelin, K., Thompson, N. W., Hoog, A., Weber, G., Farnebo, L.-O., Larsson, C. <strong>Alterations of the MEN1 gene in sporadic parathyroid tumors.</strong> J. Clin. Endocr. Metab. 83: 2627-2630, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9709922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9709922</a>] [<a href="https://doi.org/10.1210/jcem.83.8.4846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9709922">Farnebo et al. (1998)</a> screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709922" 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="#41" class="mim-tip-reference" title="Prezant, T. R., Levine, J., Melmed, S. <strong>Molecular characterization of the Men1 tumor suppressor gene in sporadic pituitary tumors.</strong> J. Clin. Endocr. Metab. 83: 1388-1391, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9543172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9543172</a>] [<a href="https://doi.org/10.1210/jcem.83.4.4859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9543172">Prezant et al. (1998)</a> screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9543172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Heppner, C., Reincke, M., Agarwal, S. K., Mora, P., Allolio, B., Burns, A. L., Spiegel, A. M., Marx, S. J. <strong>MEN1 gene analysis in sporadic adrenocortical neoplasms.</strong> J. Clin. Endocr. Metab. 84: 216-219, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920087</a>] [<a href="https://doi.org/10.1210/jcem.84.1.5388" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9920087">Heppner et al. (1999)</a> studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the role of the MEN1 gene in sporadic lipomas, <a href="#49" class="mim-tip-reference" title="Vortmeyer, A. O., Boni, R., Pak, E., Pack, S., Zhuang, Z. <strong>Multiple endocrine neoplasia 1 gene alterations in MEN1-associated and sporadic lipomas. (Letter)</strong> J. Nat. Cancer Inst. 90: 398-399, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9498491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9498491</a>] [<a href="https://doi.org/10.1093/jnci/90.5.398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9498491">Vortmeyer et al. (1998)</a> analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (<a href="#0017">613733.0017</a>). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9498491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, <a href="#33" class="mim-tip-reference" title="Kjellman, M., Roshani, L., Teh, B. T., Kallioniemi, O.-P., Hoog, A., Gray, S., Farnebo, L.-O., Holst, M., Backdahl, M., Larsson, C. <strong>Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.</strong> J. Clin. Endocr. Metab. 84: 730-735, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10022445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10022445</a>] [<a href="https://doi.org/10.1210/jcem.84.2.5506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10022445">Kjellman et al. (1999)</a> screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity (LOH). The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (<a href="/entry/160980">160980</a>) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10022445" 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>Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. <a href="#25" class="mim-tip-reference" title="Gisselsson, D., Hoglund, M., Mertens, F., Del Cin, P., Mandahl, N. <strong>Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region: metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics.</strong> Am. J. Path. 155: 61-66, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10393837[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)65099-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393837">Gisselsson et al. (1999)</a> analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in 4 cases also in the ostensibly normal homologs, resulting in homozygous loss of several loci. Among these, the MEN1 gene was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all 5 cases, adding to previous evidence for a second tumor suppressor locus in 11q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10393837" 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="#45" class="mim-tip-reference" title="Tahara, H., Imanishi, Y., Yamada, T., Tsujimoto, Y., Tabata, T., Inoue, T., Inaba, M., Morii, H., Nishizawa, Y. <strong>Rare somatic inactivation of the multiple endocrine neoplasia type 1 gene in secondary hyperparathyroidism of uremia.</strong> J. Clin. Endocr. Metab. 85: 4113-4117, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11095441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11095441</a>] [<a href="https://doi.org/10.1210/jcem.85.11.6950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11095441">Tahara et al. (2000)</a> analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, <a href="/entry/608455">608455</a>; D11S4946; and D11S449), and for mutations of the MEN1-coding exons by PCR-based SSCP analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion in MEN1. They inferred that this mutation would result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathologic characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11095441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Sato, K., Obara, T., Yamazaki, K., Kanbe, M., Nakajima, K., Yamada, A., Yanagisawa, T., Kato, Y., Nishikawa, T., Takano, K. <strong>Somatic mutations of the MEN1 gene and microsatellite instability in a case of tertiary hyperparathyroidism occurring during high phosphate therapy for acquired, hypophosphatemic osteomalacia.</strong> J. Clin. Endocr. Metab. 86: 5564-5571, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11701736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11701736</a>] [<a href="https://doi.org/10.1210/jcem.86.11.7978" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11701736">Sato et al. (2001)</a> reported a male patient with adult-onset, hypophosphatemic osteomalacia who had been treated with 1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary hyperparathyroidism developed. Sequence analysis of the coding exons of the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic parathyroid glands, accompanied by loss of heterozygosity at the 11q13 locus in 1 gland. These findings suggested that the repeated increase in serum phosphate concentrations for a prolonged period may be related to tumorigenesis of the parathyroid gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11701736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Jiao, Y., Shi, C., Edil, B. H., de Wilde, R. F., Klimstra, D. S., Maitra, A., Schulick, R. D., Tang, L. H., Wolfgang, C. L., Choti, M. A., Velculescu, V. E., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Hruban, R. H., Papadopoulos, N. <strong>DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.</strong> Science 331: 1199-1203, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21252315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21252315</a>] [<a href="https://doi.org/10.1126/science.1200609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21252315">Jiao et al. (2011)</a> explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death domain-associated protein, <a href="/entry/603186">603186</a>) and ATRX (<a href="/entry/300032">300032</a>). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. <a href="#31" class="mim-tip-reference" title="Jiao, Y., Shi, C., Edil, B. H., de Wilde, R. F., Klimstra, D. S., Maitra, A., Schulick, R. D., Tang, L. H., Wolfgang, C. L., Choti, M. A., Velculescu, V. E., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Hruban, R. H., Papadopoulos, N. <strong>DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.</strong> Science 331: 1199-1203, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21252315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21252315</a>] [<a href="https://doi.org/10.1126/science.1200609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21252315">Jiao et al. (2011)</a> also found mutations in genes in the mTOR (<a href="/entry/601231">601231</a>) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21252315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To examine the role of MEN1 in tumor formation, <a href="#15" class="mim-tip-reference" title="Crabtree, J. S., Scacheri, P. C., Ward, J. M., Garrett-Beal, L., Emmert-Buck, M. R., Edgemon, K. A., Lorang, D., Libutti, S. K., Chandrasekharapp a, S. C., Marx, S. J., Spiegel, A. M., Collins, F. S. <strong>A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.</strong> Proc. Nat. Acad. Sci. 98: 1118-1123, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11158604[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.98.3.1118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158604">Crabtree et al. (2001)</a> generated a mouse model through homologous recombination of the mouse homolog Men1. Homozygous null mice died in utero at embryonic days 11.5 to 12.5, whereas heterozygous mice developed features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets showed a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas were frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary were seen by 16 months. All of the tumors tested showed loss of the wildtype Men1 allele, further supporting the role of MEN1 as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158604" 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="#8" class="mim-tip-reference" title="Busygina, V., Suphapeetiporn, K., Marek, L. R., Stowers, R. S., Xu, T., Bale, A. E. <strong>Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.</strong> Hum. Molec. Genet. 13: 2399-2408, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333582</a>] [<a href="https://doi.org/10.1093/hmg/ddh271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15333582">Busygina et al. (2004)</a> generated a null allele of Mnn1, the Drosophila homolog of the MEN1 gene, and showed that homozygous inactivation resulted in morphologically normal flies that are hypersensitive to ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and cisplatinum). The spectrum of agents to which mutant flies were sensitive and analysis of the molecular mechanisms of this sensitivity suggested a defect in nucleotide excision repair. Drosophila Mnn1 mutants had an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats (LATS1; <a href="/entry/603473">603473</a>), which is a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. <a href="#8" class="mim-tip-reference" title="Busygina, V., Suphapeetiporn, K., Marek, L. R., Stowers, R. S., Xu, T., Bale, A. E. <strong>Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.</strong> Hum. Molec. Genet. 13: 2399-2408, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333582</a>] [<a href="https://doi.org/10.1093/hmg/ddh271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15333582">Busygina et al. (2004)</a> concluded that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA1 (<a href="/entry/113705">113705</a>) and MSH2 (<a href="/entry/609309">609309</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15333582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To examine the potential role of Men1 in hematopoiesis, <a href="#14" class="mim-tip-reference" title="Chen, Y.-X., Yan, J., Keeshan, K., Tubbs, A. T., Wang, H., Silva, A., Brown, E. J., Hess, J. L., Pear, W. S., Hua, X. <strong>The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression.</strong> Proc. Nat. Acad. Sci. 103: 1018-1023, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16415155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0510347103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415155">Chen et al. (2006)</a> targeted Men1 excision in a temporally-controlled manner. Disruption of Men1 in mice after birth gradually led to decreased total white blood cell count but did not significantly reduce red blood cell numbers. There was also reduced Hoxa9 (<a href="/entry/142956">142956</a>) expression and reduced colony formation by hematopoietic progenitors. <a href="#14" class="mim-tip-reference" title="Chen, Y.-X., Yan, J., Keeshan, K., Tubbs, A. T., Wang, H., Silva, A., Brown, E. J., Hess, J. L., Pear, W. S., Hua, X. <strong>The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression.</strong> Proc. Nat. Acad. Sci. 103: 1018-1023, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16415155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0510347103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415155">Chen et al. (2006)</a> determined that Men1 directly activated Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitated the methylation of histone H3 on lysine-4 (H3K4), and recruited the methylated H3K4-binding protein Chd1 (<a href="/entry/602118">602118</a>) to the locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415155" 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 addition to cancer risk, MEN1 patients have been reported to have neurologic symptoms, including depression (MDD; <a href="/entry/608516">608516</a>) (<a href="#3" class="mim-tip-reference" title="Aoki, A., Tsukada, T., Yasuda, H., Kayashima, S., Nagase, T., Ito, T., Suzuki, T., Matsukuma, S., Kuwabara, N., Yoshimoto, K., Yamaguchi, K. <strong>Multiple endocrine neoplasia type 1 presented with manic-depressive disorder: a case report with an identified MEN1 gene mutation.</strong> Jpn. J. Clin. Oncol. 27: 419-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9438006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9438006</a>] [<a href="https://doi.org/10.1093/jjco/27.6.419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9438006">Aoki et al., 1997</a>). <a href="#35" class="mim-tip-reference" title="Leng, L., Zhuang, K., Liu, Z., Huang, C., Gao, Y., Chen G., Lin, H., Hu, Y., Wu, D., Shi, M., Xie, W., Sun, H., and 12 others. <strong>Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation.</strong> Neuron 100: 551-563, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30220511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30220511</a>] [<a href="https://doi.org/10.1016/j.neuron.2018.08.031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30220511">Leng et al. (2018)</a> studied a mouse model of MEN1 loss of function and demonstrated that menin deficiency increased Nfkb (<a href="/entry/164011">164011</a>)-induced Il1b (<a href="/entry/147720">147720</a>) levels in astroglia of male mice subjected to mild stress and lipopolysaccharide (LPS) injections. Whereas germline knockout mice died shortly after birth, a brain-specific knockout for Men1 was viable, had reduced Men1 astroglial expression, and showed depressive-like behaviors such as reduced mobility and impaired sociability. When animals were treated with an Nfkb inhibitor or an Il1b receptor antagonist, the depressive phenotype was rescued. <a href="#35" class="mim-tip-reference" title="Leng, L., Zhuang, K., Liu, Z., Huang, C., Gao, Y., Chen G., Lin, H., Hu, Y., Wu, D., Shi, M., Xie, W., Sun, H., and 12 others. <strong>Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation.</strong> Neuron 100: 551-563, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30220511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30220511</a>] [<a href="https://doi.org/10.1016/j.neuron.2018.08.031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30220511">Leng et al. (2018)</a> also genotyped a human cohort of 1,032 MDD patients and identified one SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs375804228;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs375804228</a>) with an odds ratio of 3.2. Transfection studies of this variant, a G503D substitution in exon 10, in HEK293T cells showed reduced p65 (RELA; <a href="/entry/164014">164014</a>) DNA binding. <a href="#35" class="mim-tip-reference" title="Leng, L., Zhuang, K., Liu, Z., Huang, C., Gao, Y., Chen G., Lin, H., Hu, Y., Wu, D., Shi, M., Xie, W., Sun, H., and 12 others. <strong>Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation.</strong> Neuron 100: 551-563, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30220511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30220511</a>] [<a href="https://doi.org/10.1016/j.neuron.2018.08.031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30220511">Leng et al. (2018)</a> concluded that astroglial menin deficiency or mutation is able to produce neuroinflammation contributing to MDD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30220511+9438006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="allelicVariants" class="mim-anchor"></a>
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<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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</span>
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<strong>35 Selected Examples</a>):</strong>
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<p />
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<a href="/allelicVariants/613733" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=613733[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<a id="0001" class="mim-anchor"></a>
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<strong>.0001 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, LEU22ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894256 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894256;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=rs104894256" 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=rs104894256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018157 OR RCV000182402" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018157, RCV000182402" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018157...</a>
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<span class="mim-text-font">
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<p>In a proband with multiple endocrine neoplasia type I (MEN1; <a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous missense mutation in the MEN1 gene, changing residue 22 from leucine to arginine (L22R). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0002" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0002 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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</span>
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</h4>
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MEN1, 4-BP DEL, NT357
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776841;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=rs587776841" 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=rs587776841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018173 OR RCV000182434 OR RCV000206170 OR RCV000491114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018173, RCV000182434, RCV000206170, RCV000491114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018173...</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous deletion of 4 bp starting from nucleotide 357 in the MEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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<div style="float: left;">
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MEN1, 1-BP DEL, 416C
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs794728639 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728639;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=rs794728639" 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=rs794728639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018159 OR RCV000182435 OR RCV000491671" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018159, RCV000182435, RCV000491671" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018159...</a>
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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 probands from 2 families with MEN1 (<a href="/entry/131100">131100</a>) not known to be related, <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous 1-bp deletion of nucleotide 416, a cytidine, in the MEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" 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>
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<div>
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<br />
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<a id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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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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<div style="float: left;">
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MEN1, 3-BP DEL, LYS119DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs794728657 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728657;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=rs794728657" 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=rs794728657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018160 OR RCV000182460 OR RCV000491280" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018160, RCV000182460, RCV000491280" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018160...</a>
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<div>
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<span class="mim-text-font">
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous 3-bp deletion in the MEN1 gene, resulting in deletion of lys119. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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<div style="float: left;">
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MEN1, 1-BP DEL, 512C
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</div>
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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> rs397515385 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515385;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/rs397515385?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=rs397515385" 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=rs397515385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018161 OR RCV000182436 OR RCV000491332" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018161, RCV000182436, RCV000491332" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018161...</a>
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<span class="mim-text-font">
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<p>In 2 probands with MEN1 (<a href="/entry/131100">131100</a>) from families not known to be related, <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous deletion of nucleotide 512, a cytidine, in the MEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" 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>.0006 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs104894257 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894257;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=rs104894257" 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=rs104894257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894258 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894258;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=rs104894258" 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=rs104894258" 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=RCV000018162" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018162" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018162</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous missense mutation in the MEN1 gene, converting codon 198 from tryptophan to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, 4-BP DEL, NT735
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs794728640 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728640;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=rs794728640" 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=rs794728640" 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=RCV000018163 OR RCV000182437 OR RCV000491752" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018163, RCV000182437, RCV000491752" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018163...</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous deletion of 4 bp in the MEN1 gene, starting from nucleotide position 735. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, 1-BP DEL, 1132G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555164986 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555164986;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=rs1555164986" 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=rs1555164986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000509058" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000509058" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000509058</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous deletion of nucleotide 1132, a guanine, in the MEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, 3-BP DEL, GLU363DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025185 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025185;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=rs869025185" 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=rs869025185" 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=RCV000018165 OR RCV000255250 OR RCV000491660" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018165, RCV000255250, RCV000491660" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018165...</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous 3-bp deletion in the MEN1 gene, resulting in deletion of glu363. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0010 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, TRP436ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894259 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894259;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=rs104894259" 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=rs104894259" 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=RCV000018166 OR RCV000255755 OR RCV004018639" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018166, RCV000255755, RCV004018639" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018166...</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous missense mutation in the MEN1 gene, converting codon 436 from tryptophan to arginine (W436R). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs104894260 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894260;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=rs104894260" 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=rs104894260" 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=RCV000018167 OR RCV000518947" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018167, RCV000518947" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018167...</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous nonsense mutation in the MEN1 gene, converting codon 436 from tryptophan to stop (W436X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<strong>.0012 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, ARG527TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894261 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894261;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=rs104894261" 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=rs104894261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018168 OR RCV000182423 OR RCV000491431 OR RCV004813043" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018168, RCV000182423, RCV000491431, RCV004813043" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018168...</a>
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<p>In a proband with MEN1 (<a href="/entry/131100">131100</a>), <a href="#13" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Positional cloning of the gene for multiple endocrine neoplasia-type 1.</strong> Science 276: 404-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9103196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9103196</a>] [<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified a heterozygous nonsense mutation at codon 527 of the MEN1 gene, converting arginine to stop (R527X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0013 PARATHYROID ADENOMA, SOMATIC</strong>
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</h4>
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MEN1, GLU26LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28931612 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28931612;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=rs28931612" 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=rs28931612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018169 OR RCV000490040 OR RCV000817082" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018169, RCV000490040, RCV000817082" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018169...</a>
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<span class="mim-text-font">
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<p>Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 1 in 2,000. <a href="#28" class="mim-tip-reference" title="Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., Emmert-Buck, M. R., Guru, S. C., Manickam, P., Olufemi, S.-E., Skarulis, M. C., Doppman, J. L., Alexander, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Somatic mutation of the MEN1 gene in parathyroid tumours.</strong> Nature Genet. 16: 375-378, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241276</a>] [<a href="https://doi.org/10.1038/ng0897-375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241276">Heppner et al. (1997)</a> stated that in more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as MEN1. In most cases, however, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal. Approximately 30% of sporadic parathyroid tumors show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumor suppressor gene. Among 33 sporadic parathyroid tumors (see <a href="/entry/131100">131100</a>), <a href="#28" class="mim-tip-reference" title="Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., Emmert-Buck, M. R., Guru, S. C., Manickam, P., Olufemi, S.-E., Skarulis, M. C., Doppman, J. L., Alexander, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Somatic mutation of the MEN1 gene in parathyroid tumours.</strong> Nature Genet. 16: 375-378, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241276</a>] [<a href="https://doi.org/10.1038/ng0897-375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241276">Heppner et al. (1997)</a> found a somatic MEN1 gene mutation in 7 (21%), while the corresponding MEN1 germline sequence was normal in each patient. All tumors with MEN1 gene mutations showed LOH on 11q13, making the tumor cells hemi- or homozygous for the mutant allele. They concluded that somatic MEN1 gene mutations contribute to tumorigenesis in a substantial number of parathyroid tumors not associated with the MEN1 syndrome, thus fulfilling the characteristics of the Knudson model. In 1 of the 7 cases with a somatic cell mutation, a GAG-to-AAG change was found in codon 26 (E26K). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0014 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, GLN260TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894266 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894266;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=rs104894266" 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=rs104894266" 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=RCV000018170 OR RCV000491298 OR RCV004748527 OR RCV004998100" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018170, RCV000491298, RCV004748527, RCV004998100" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018170...</a>
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<p>In a sporadic case of MEN1 (<a href="/entry/131100">131100</a>), <a href="#2" class="mim-tip-reference" title="Agarwal, S. K., Kester, M. B., Debelenko, L. V., Heppner, C., Emmert-Buck, M. R., Skarulis, M. C., Doppman, J. L., Kim, Y. S., Lubensky, I. A., Zhuang, Z., Green, J. S., Guru, S. C., Manickam, P., Olufemi, S.-E., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. <strong>Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.</strong> Hum. Molec. Genet. 6: 1169-1175, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9215689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9215689</a>] [<a href="https://doi.org/10.1093/hmg/6.7.1169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9215689">Agarwal et al. (1997)</a> identified a heterozygous nonsense mutation in the MEN1 gene, converting glutamine-260 to stop (Q260X). The patient had multiple tumors of the parathyroid glands, Zollinger-Ellison syndrome, and growth hormone-prolactin macroadenoma of the anterior pituitary gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9215689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<strong>.0015 CARCINOID TUMOR OF LUNG</strong>
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MEN1, 1-BP INS, 1650C
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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> rs767319284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767319284;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/rs767319284?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=rs767319284" 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=rs767319284" 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=RCV000018171 OR RCV000269197 OR RCV000491230 OR RCV000548407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018171, RCV000269197, RCV000491230, RCV000548407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018171...</a>
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<p>Lung carcinoids occur sporadically and rarely in association with MEN1 (see <a href="/entry/131100">131100</a>). <a href="#17" class="mim-tip-reference" title="Debelenko, L. V., Brambilla, E., Agarwal, S. K., Swalwell, J. I., Kester, M. B., Lubensky, I. A., Zhuang, Z., Guru, S. C., Manickam, P., Olufemi, S.-E., Chandrasekharappa, S. C., Crabtree, J. S., Kim, Y. S., Heppner, C., Burns, A. L., Spiegel, A. M., Marx, S. J., Liotta, L. A., Collins, F. S., Travis, W. D., Emmert-Buck, M. R. <strong>Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung.</strong> Hum. Molec. Genet. 6: 2285-2290, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361035</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361035">Debelenko et al. (1997)</a> studied 11 sporadic lung carcinoids for LOH in 1 locus and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from an MEN1 patient was studied. In 4 of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All 4 tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1-bp insertion (1650insC) , a 1-bp deletion, a 13-bp deletion, and a single nucleotide substitution affecting a donor splice site. Each mutation predicted truncation or potentially complete loss of MEN1. The remaining 7 tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at 11q13 and a complex germline MEN1 gene mutation. The findings of this study represented the first defined genetic alteration in carcinoids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9361035" 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>.0016 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs104894267 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894267;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=rs104894267" 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=rs104894267" 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=RCV000018172 OR RCV000129526 OR RCV000182421" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018172, RCV000129526, RCV000182421" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018172...</a>
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<p><a href="#38" class="mim-tip-reference" title="Olufemi, S.-E., Green, J. S., Manickam, P., Guru, S. C., Agarwal, S. K., Kester, M. B., Dong, Q., Burns, A. L., Spiegel, A. M., Marx, S. J., Collins, F. S., Chandrasekharappa, S. C. <strong>Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1-Burin) in four kindreds from Newfoundland.</strong> Hum. Mutat. 11: 264-269, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9554741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9554741</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:4<264::AID-HUMU2>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9554741">Olufemi et al. (1998)</a> demonstrated an arg460-to-ter mutation (R460X) in the MEN1 gene in affected members of 4 families with MEN1 (<a href="/entry/131100">131100</a>), originally described by <a href="#19" class="mim-tip-reference" title="Farid, N. R., Buehler, S., Russell, N. A., Maroun, F. B., Allerdice, P., Smyth, H. S. <strong>Prolactinomas in familial multiple endocrine neoplasia syndrome type I: relationship to HLA and carcinoid tumors.</strong> Am. J. Med. 69: 874-880, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6108714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6108714</a>] [<a href="https://doi.org/10.1016/s0002-9343(80)80013-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6108714">Farid et al. (1980)</a> and <a href="#6" class="mim-tip-reference" title="Bear, J. C., Briones-Urbina, R., Fahey, J. F., Farid, N. R. <strong>Variant multiple endocrine neoplasia I (MEN I-Burin): further studies and non-linkage to HLA.</strong> Hum. Hered. 35: 15-20, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2857681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2857681</a>] [<a href="https://doi.org/10.1159/000153508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2857681">Bear et al. (1985)</a>. Affected members had prolactinomas, carcinoid tumors of the lung and thymus, and hyperparathyroidism. The disorder was called the MEN1 Burin variant by <a href="#6" class="mim-tip-reference" title="Bear, J. C., Briones-Urbina, R., Fahey, J. F., Farid, N. R. <strong>Variant multiple endocrine neoplasia I (MEN I-Burin): further studies and non-linkage to HLA.</strong> Hum. Hered. 35: 15-20, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2857681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2857681</a>] [<a href="https://doi.org/10.1159/000153508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2857681">Bear et al. (1985)</a>. All 4 families lived in the Burin peninsula of Newfoundland. The ancestors of each of the 4 independently identified families came from a group of very small, isolated, now-abandoned communities within a 20-mile radius on the north shore of Fortune Bay. No single common ancestor was identified by examination of genealogic records, but there were common surnames in the earliest generations recorded. By haplotype analysis, <a href="#38" class="mim-tip-reference" title="Olufemi, S.-E., Green, J. S., Manickam, P., Guru, S. C., Agarwal, S. K., Kester, M. B., Dong, Q., Burns, A. L., Spiegel, A. M., Marx, S. J., Collins, F. S., Chandrasekharappa, S. C. <strong>Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1-Burin) in four kindreds from Newfoundland.</strong> Hum. Mutat. 11: 264-269, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9554741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9554741</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:4<264::AID-HUMU2>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9554741">Olufemi et al. (1998)</a> demonstrated a common haplotype over a 2.5-Mb region that was shared by affected members of all 4 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6108714+9554741+2857681" 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>.0017 LIPOMA, SOMATIC</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018173 OR RCV000182434 OR RCV000206170 OR RCV000491114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018173, RCV000182434, RCV000206170, RCV000491114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018173...</a>
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<p>In a case of sporadic lipoma (see <a href="/entry/131100">131100</a>), <a href="#49" class="mim-tip-reference" title="Vortmeyer, A. O., Boni, R., Pak, E., Pack, S., Zhuang, Z. <strong>Multiple endocrine neoplasia 1 gene alterations in MEN1-associated and sporadic lipomas. (Letter)</strong> J. Nat. Cancer Inst. 90: 398-399, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9498491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9498491</a>] [<a href="https://doi.org/10.1093/jnci/90.5.398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9498491">Vortmeyer et al. (1998)</a> identified deletion of TGTC from exon 2 of the MEN1 gene. The deletion was not found in constitutional DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9498491" 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">rs121913034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913034;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=rs121913034" 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=rs121913034" 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=RCV000018174" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018174" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018174</a>
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<p>Angiofibromas are benign cutaneous tumors that can occur sporadically or as multiple lesions in association with inherited diseases. As a rule, multiple facial angiofibromas are thought to be specific for tuberous sclerosis (see <a href="/entry/191100">191100</a>); however, <a href="#16" class="mim-tip-reference" title="Darling, T. N., Skarulis, M. C., Steinberg, S. M., Marx, S. J., Spiegel, A. M., Turner, M. <strong>Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.</strong> Arch. Derm. 133: 853-857, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9236523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9236523</a>]" pmid="9236523">Darling et al. (1997)</a> showed that angiofibromas may also be associated with multiple endocrine neoplasia type I. <a href="#7" class="mim-tip-reference" title="Boni, R., Vortmeyer, A. O., Pack, S., Park, W.-S., Burg, G., Hofbauer, G., Darling, T., Liotta, L., Zhuang, Z. <strong>Somatic mutations of the MEN1 tumor suppressor gene detected in sporadic angiofibromas. (Letter)</strong> J. Invest. Derm. 111: 539-540, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9740255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9740255</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00317.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9740255">Boni et al. (1998)</a> investigated whether the MEN1 gene might be implicated in sporadic angiofibromas. For this purpose, they analyzed 19 sporadic facial angiofibromas (see <a href="/entry/131100">131100</a>) for mutation in the MEN1 gene using PCR-based SSCP and sequencing analysis. All patients had a negative family history for tuberous sclerosis and MEN1 disease. Aberrant bands were detected in 2 tumors: one mutation was an A-to-T transversion at nucleotide 517 changing codon 135 from AAG (lys) to TAG (ile); the second mutation was a transversion of GG to AA at nucleotides 1184 and 1185 resulting in a change of codon 358 from GAG (glu) to GAA (also glu) and codon 359 from GAG (glu) to AAG (lys) (<a href="#0019">613733.0019</a>). The mutations were in exons 2 and 8, respectively. The mutations were observed only in tumor DNA and not in normal control tissue. LOH analysis, performed using 2 polymorphic markers flanking the MEN1 gene, showed no LOH in any of the 19 angiofibromas, including the 2 displaying mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9740255+9236523" 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">rs267607234 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607234;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=rs267607234" 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=rs267607234" 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=RCV000018175" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018175" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018175</a>
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<p>See <a href="#0018">613733.0018</a> and <a href="#7" class="mim-tip-reference" title="Boni, R., Vortmeyer, A. O., Pack, S., Park, W.-S., Burg, G., Hofbauer, G., Darling, T., Liotta, L., Zhuang, Z. <strong>Somatic mutations of the MEN1 tumor suppressor gene detected in sporadic angiofibromas. (Letter)</strong> J. Invest. Derm. 111: 539-540, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9740255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9740255</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00317.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9740255">Boni et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9740255" 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>.0020 HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY, MEN1 VARIANT</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">rs104894268 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894268;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=rs104894268" 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=rs104894268" 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=RCV000018176 OR RCV001753420" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018176, RCV001753420" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018176...</a>
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<p>In a Caucasian English family in which 7 family members from 2 generations had primary hyperparathyroidism, <a href="#46" class="mim-tip-reference" title="Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E. <strong>A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)</strong> Am. J. Hum. Genet. 63: 1544-1549, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792884</a>] [<a href="https://doi.org/10.1086/302097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792884">Teh et al. (1998)</a> found that affected members had a germline missense mutation in codon 255 (GAG to AAG) of exon 4, causing an amino acid change from glutamic acid to lysine (glu255 to lys). The G-to-A transition at nucleotide 763 of the cDNA also gave rise to a HindIII restriction cleavage site for the mutant allele. This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1 (<a href="/entry/131100">131100</a>). The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, <a href="#46" class="mim-tip-reference" title="Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E. <strong>A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)</strong> Am. J. Hum. Genet. 63: 1544-1549, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792884</a>] [<a href="https://doi.org/10.1086/302097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792884">Teh et al. (1998)</a> demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792884" 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>.0021 HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY, MEN1 VARIANT</strong>
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MEN1, VAL184GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894262 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894262;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=rs104894262" 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=rs104894262" 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=RCV000018177" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018177" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018177</a>
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<p>In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas (see MEN1, <a href="/entry/131100">131100</a>), <a href="#22" class="mim-tip-reference" title="Fujimori, M., Shirahama, S., Sakurai, A., Hashizume, K., Hama, Y., Ito, K., Shingu, K., Kobayashi, S., Amano, J., Fukushima, Y. <strong>Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism.</strong> Am. J. Med. Genet. 80: 221-222, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843042</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19981116)80:3<221::aid-ajmg8>3.0.co;2-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843042">Fujimori et al. (1998)</a> demonstrated a T-to-A transversion at codon 184 in exon 3, predicted to result in an amino acid change from valine to glutamic acid (V184E). (<a href="#22" class="mim-tip-reference" title="Fujimori, M., Shirahama, S., Sakurai, A., Hashizume, K., Hama, Y., Ito, K., Shingu, K., Kobayashi, S., Amano, J., Fukushima, Y. <strong>Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism.</strong> Am. J. Med. Genet. 80: 221-222, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843042</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19981116)80:3<221::aid-ajmg8>3.0.co;2-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843042">Fujimori et al. (1998)</a> incorrectly described the nucleotide change as a transition and the amino acid change as valine to glutamine. The change was presumably GTG (val) to GAG (glu); this was confirmed by <a href="#23" class="mim-tip-reference" title="Fujimori, M. <strong>Personal Communication.</strong> Matsumoto, Japan 1/5/1999."None>Fujimori (1999)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0022" class="mim-anchor"></a>
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<strong>.0022 ADRENAL ADENOMA, SOMATIC</strong>
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MEN1, THR552SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913035 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913035;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=rs121913035" 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=rs121913035" 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=RCV000018178" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018178" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018178</a>
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<p>Because loss of heterozygosity on 11q13 occurs in about 20% of sporadic adrenal neoplasms, and adrenal lesions, mostly benign, occur in up to 40% of patients from MEN1 kindreds, MEN1 was considered a prime candidate gene in these lesions. <a href="#43" class="mim-tip-reference" title="Schulte, K.-M., Heinze, M., Mengel, M., Simon, D., Scheuring, S., Kohrer, K., Roher, H.-D. <strong>MEN I gene mutations in sporadic adrenal adenomas.</strong> Hum. Genet. 105: 603-610, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647896</a>] [<a href="https://doi.org/10.1007/s004399900193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647896">Schulte et al. (1999)</a> studied 15 patients with sporadic adrenal adenoma (see <a href="/entry/131100">131100</a>) and 1 patient with multinodular hyperplasia. Of the 16 patients, 4 had incidentally discovered masses ('incidentalomas'), 5 had Conn syndrome, 6 had Cushing syndrome (<a href="/entry/219080">219080</a>), and 9 had high sex hormone production. <a href="#43" class="mim-tip-reference" title="Schulte, K.-M., Heinze, M., Mengel, M., Simon, D., Scheuring, S., Kohrer, K., Roher, H.-D. <strong>MEN I gene mutations in sporadic adrenal adenomas.</strong> Hum. Genet. 105: 603-610, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647896</a>] [<a href="https://doi.org/10.1007/s004399900193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647896">Schulte et al. (1999)</a> performed direct DNA sequencing of the menin gene in 14 sporadic adrenal adenomas and 1 case of adrenal hyperplasia. They identified 1 heterozygous missense mutation, thr552 to ser, in a hormonally inactive adrenal adenoma. This is another example of mutation in the MEN1 gene causing a sporadic form of tumors that occur as part of MEN1 disease. Other examples include parathyroid adenoma, gastrinoma, and bronchial carcinoid tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647896" 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>.0023 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, HIS139ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894263;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=rs104894263" 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=rs104894263" 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=RCV000018179 OR RCV000491226 OR RCV004998101" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018179, RCV000491226, RCV004998101" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018179...</a>
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<p><a href="#44" class="mim-tip-reference" title="Stratakis, C. A., Schussheim, D. H., Freedman, S. M., Keil, M. F., Pack, S. D., Agarwal, S. K., Skarulis, M. C., Weil, R. J., Lubensky, I. A., Zhuang, Z., Oldfield, E. H., Marx, S. J. <strong>Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1.</strong> J. Clin. Endocr. Metab. 85: 4776-4780, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134142</a>] [<a href="https://doi.org/10.1210/jcem.85.12.7064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11134142">Stratakis et al. (2000)</a> reported a 2.3-cm pituitary macroadenoma in a 5-year-old boy with familial MEN1 (<a href="/entry/131100">131100</a>). He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. Germline DNA of the propositus and his affected relatives had a heterozygous point mutation in the MEN1 gene that led to a his139-to-asp substitution. The patient had no other detectable germline mutations in either MEN1 allele. DNA sequencing and FISH with a MEN1 genomic DNA sequence probe each demonstrated 1 copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 'second hit' as a tumor cause. The authors stated that this patient represents the earliest presentation of any morbid endocrine tumor in MEN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11134142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0024" class="mim-anchor"></a>
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<strong>.0024 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs794728625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728625;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=rs794728625" 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=rs794728625" 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=RCV000182415 OR RCV000205749 OR RCV002408796" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000182415, RCV000205749, RCV002408796" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000182415...</a>
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<p>In 7 unrelated families with MEN1 (<a href="/entry/131100">131100</a>), <a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> found a G-to-A transition at nucleotide 5168 in intron 4 of the MEN1 gene, which resulted in a novel acceptor splice site in intron 4. Use of this novel acceptor site leads to incorporation of the 7 bp 5-prime to the naturally occurring acceptor splice site, with resultant frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" 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>.0025 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018160 OR RCV000182460 OR RCV000491280" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018160, RCV000182460, RCV000491280" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018160...</a>
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<p>In affected members of a family with MEN1 (<a href="/entry/131100">131100</a>), <a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> found heterozygosity for a 3-bp in-frame deletion of GAA at codon 118-119 of the MEN1 gene. <a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> noted that this mutation had been reported in 8 other MEN1 families; this mutation had been recorded by <a href="#5" class="mim-tip-reference" title="Bassett, J. H. D., Forbes, S. A., Pannett, A. A. J., Lloyd, S. E., Christie, P. T., Wooding, C., Harding, B., Besser, G. M., Edwards, C. R., Monson, J. P., Sampson, J., Wass, J. A. H., Wheeler, M. H., Thakker, R. V. <strong>Characterization of mutations in patients with multiple endocrine neoplasia type 1.</strong> Am. J. Hum. Genet. 62: 232-244, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463336</a>] [<a href="https://doi.org/10.1086/301729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463336">Bassett et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9463336+12050235" 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>.0026 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, 4-BP DEL, 4480CAGT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1941851693 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1941851693;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=rs1941851693" 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=rs1941851693" 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=RCV000018182" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018182" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018182</a>
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<p>In affected members of a family with MEN1 (<a href="/entry/131100">131100</a>), <a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> found heterozygosity for a 4-bp deletion involving codons 209 to 211 in exon 3 of the MEN1 gene. The mutation was predicted to result in frameshift and premature termination after 11 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" 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>.0027 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs104894264 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894264;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=rs104894264" 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=rs104894264" 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=RCV000018183 OR RCV000490854 OR RCV001269702" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018183, RCV000490854, RCV001269702" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018183...</a>
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<p>In affected members of 2 families with MEN1 (<a href="/entry/131100">131100</a>), <a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> found a heterozygous G-to-A transition at nucleotide 7262 in exon 9 of the MEN1 gene, resulting in an asp418-to-asn (D418N) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" 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>.0028 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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> rs767319284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767319284;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/rs767319284?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=rs767319284" 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=rs767319284" 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=RCV000182439 OR RCV000228926 OR RCV001012050" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000182439, RCV000228926, RCV001012050" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000182439...</a>
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<p>In 1 family with MEN1 (<a href="/entry/131100">131100</a>), <a href="#48" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. <strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong> J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050235">Turner et al. (2002)</a> found heterozygosity for a deletion of a C nucleotide at position 7773 in exon 10 of the MEN1 gene, resulting in a frameshift and premature termination 42 amino acids after codon 516. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0029" class="mim-anchor"></a>
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<strong>.0029 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs104894265 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894265;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=rs104894265" 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=rs104894265" 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=RCV000018185" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018185" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018185</a>
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<p>In a woman with MEN1 (<a href="/entry/131100">131100</a>), <a href="#4" class="mim-tip-reference" title="Balogh, K., Patocs, A., Majnik, J., Varga, F., Illyes, G., Hunyady, L., Racz, K. <strong>Unusual presentation of multiple endocrine neoplasia type 1 in a young woman with a novel mutation of the MEN1 gene.</strong> J. Hum. Genet. 49: 380-386, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15205994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15205994</a>] [<a href="https://doi.org/10.1007/s10038-004-0163-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15205994">Balogh et al. (2004)</a> identified a heterozygous C-to-A transversion in exon 8 of the MEN1 gene, resulting in a cys354-to-ter (C354X) mutation. The woman was first investigated at the age of 25 years for abdominal discomfort and left upper abdominal pain. A giant pancreatic tumor was identified by abdominal ultrasonography and CT scan. The diagnosis of a clinically nonfunctioning pancreatic neuroendocrine tumor was established by clinical studies, and the patient underwent a distal pancreatectomy. Histology proved a well-differentiated multinodular neuroendocrine tumor of the pancreas. During surgery, a subcutaneous lipoma was removed from the abdominal wall. Two days later, the patient developed primary hyperparathyroidism, and 2 enlarged parathyroid glands were surgically removed. Her family history was unremarkable, except for an unknown disorder in her father that had caused an early death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15205994" 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>.0030 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs1555165485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555165485;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=rs1555165485" 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=rs1555165485" 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=RCV000632129" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000632129" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000632129</a>
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<p>In 3 members of a Japanese family with MEN1 (<a href="/entry/131100">131100</a>) and a predisposition to insulinoma, <a href="#37" class="mim-tip-reference" title="Okamoto, H., Tamada, A., Hai, N., Doi, M., Uchimura, I., Hirata, Y., Kosugi, S. <strong>A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism.</strong> Jpn. J. Clin. Oncol. 32: 368-370, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417605</a>] [<a href="https://doi.org/10.1093/jjco/hyf079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417605">Okamoto et al. (2002)</a> identified a heterozygous germline mutation in exon 4 of the MEN1 gene, 878insCTGCAG (insertion of 6 nucleotides after nucleotide 878), resulting in the insertion of 2 amino acids, leu-gln, after amino acid 256 of the menin protein (256insLQ). The authors noted that CTGCAG is a palindromic sequence, repeated twice in the wildtype allele from nucleotides 879 to 890. <a href="#37" class="mim-tip-reference" title="Okamoto, H., Tamada, A., Hai, N., Doi, M., Uchimura, I., Hirata, Y., Kosugi, S. <strong>A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism.</strong> Jpn. J. Clin. Oncol. 32: 368-370, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417605</a>] [<a href="https://doi.org/10.1093/jjco/hyf079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417605">Okamoto et al. (2002)</a> found a significant difference (p = 0.0022) on chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas, and suggested that there may be a correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417605" 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>.0031 HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY</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">rs863223311 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223311;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=rs863223311" 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=rs863223311" 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=RCV000018187 OR RCV002381254 OR RCV003517126" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018187, RCV002381254, RCV003517126" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018187...</a>
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<p>In a Chilean family with familial isolated primary hyperparathyroidism (FIHP; <a href="/entry/145000">145000</a>), <a href="#11" class="mim-tip-reference" title="Carrasco, C. A., Gonzalez, A. A., Carvajal, C. A., Campusano, C., Oestreicher, E., Arteaga, E., Wohllk, N., Fardella, C. E. <strong>Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism.</strong> J. Clin. Endocr. Metab. 89: 4124-4129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15292357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15292357</a>] [<a href="https://doi.org/10.1210/jc.2003-032101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15292357">Carrasco et al. (2004)</a> identified a heterozygous G-to-A transition at nucleotide 7361 of the tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9+1G-A). All 11 family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and wildtype sequences. RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. The authors concluded that this mutation produces an aberrant splicing of mRNA that could lead to a truncated protein without activity, explaining the clinical picture of this patient and his family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15292357" 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>.0032 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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">rs760199250 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs760199250;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=rs760199250" 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=rs760199250" 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=RCV000018188" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018188" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018188</a>
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<p>Among 19 Finnish MEN1 (<a href="/entry/131100">131100</a>) probands, <a href="#47" class="mim-tip-reference" title="Teh, B. T., Kytola, S., Farnebo, F., Bergman, L., Wong, F. K., Weber, G., Hayward, N., Larsson, C., Skogseid, B., Beckers, A., Phelan, C., Edwards, M., and 29 others. <strong>Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.</strong> J. Clin. Endocr. Metab. 83: 2621-2626, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9709921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9709921</a>] [<a href="https://doi.org/10.1210/jcem.83.8.5059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9709921">Teh et al. (1998)</a> identified a heterozygous 1466del12 mutation in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Ebeling, T., Vierimaa, O., Kytola, S., Leisti, J., Salmela, P. I. <strong>Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.</strong> J. Clin. Endocr. Metab. 89: 3392-3396, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240620</a>] [<a href="https://doi.org/10.1210/jc.2003-031513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240620">Ebeling et al. (2004)</a> used church records and MEN1 family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 and 1657insC (<a href="#0033">613733.0033</a>). They traced the roots of 8 families with the 1466del12 mutation to a small village approximately 45 kilometers east of Oulu, where the founder couple were born in 1705 and 1709, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240620" 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>.0033 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018171 OR RCV000269197 OR RCV000491230 OR RCV000548407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018171, RCV000269197, RCV000491230, RCV000548407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018171...</a>
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<p><a href="#18" class="mim-tip-reference" title="Ebeling, T., Vierimaa, O., Kytola, S., Leisti, J., Salmela, P. I. <strong>Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.</strong> J. Clin. Endocr. Metab. 89: 3392-3396, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240620</a>] [<a href="https://doi.org/10.1210/jc.2003-031513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240620">Ebeling et al. (2004)</a> used church records and MEN1 (<a href="/entry/131100">131100</a>) family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 (<a href="#0032">613733.0032</a>) and 1657insC. Four families with the 1657incC mutation could be traced back to a couple living 200 kilometers northeast of Oulu born in 1844 and 1846, and not farther than only 4 generations from the youngest. The authors noted that while the most prevalent mutation (1466del12; <a href="#0032">613733.0032</a>) is a unique Finnish mutation, the 1657delC mutation seems to be a hotspot, as it has been found in 5 different MEN1 populations (<a href="#26" class="mim-tip-reference" title="Guo, S. S., Sawicki, M. P. <strong>Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1.</strong> Molec. Endocr. 15: 1653-1664, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11579199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11579199</a>] [<a href="https://doi.org/10.1210/mend.15.10.0717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11579199">Guo and Sawicki, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11579199+15240620" 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">rs1060499976 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060499976;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=rs1060499976" 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=rs1060499976" 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=RCV000018190 OR RCV002426511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018190, RCV002426511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018190...</a>
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<p><a href="#21" class="mim-tip-reference" title="Frank-Raue, K., Rondot, S., Hoeppner, W., Goretzki, P., Raue, F. and Meng, W. <strong>Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism.</strong> J. Clin. Endocr. Metab. 90: 4063-4067, 2005. Note: Erratum: J. Clin. Endocr. Metab. 90: 5575 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15870131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15870131</a>] [<a href="https://doi.org/10.1210/jc.2004-1759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15870131">Frank-Raue et al. (2005)</a> reported a family with coexistence of a mutation in the MEN1 gene, resulting in multiple endocrine neoplasia with recurrent hyperparathyroidism (<a href="/entry/131100">131100</a>) , and in the RET gene (Y791F; <a href="/entry/164761#0034">164761.0034</a>), which alone produced no clinical phenotype and carries a low risk of medullary thyroid carcinoma, also implicating a low incidence of pheochromocytoma and primary hyperparathyroidism. A heterozygous substitution of G to A at position +1 in intron 5 of the MEN1 gene disrupted the consensus sequence in the splice donor site. This was predicted to lead to a nonsense peptide sequence from this position and premature termination of protein synthesis. Two patients carrying both mutations had typical manifestations of MEN1; the third patient carrying both mutations, being 6 years of age at the time of the report, showed no clinical manifestations. The authors concluded that the 2 mutations do not interact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15870131" 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>.0035 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
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MEN1, IVS3DS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs794728622 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728622;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=rs794728622" 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=rs794728622" 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=RCV000032982 OR RCV002362604 OR RCV002510773" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032982, RCV002362604, RCV002510773" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032982...</a>
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<p>In affected members of a 3-generation family with MEN1 (<a href="/entry/131100">131100</a>), <a href="#9" class="mim-tip-reference" title="Canaff, L., Vanbellinghen, J.-F., Kaji, H., Goltzman, D., Hendy, G. N. <strong>Impaired transforming growth factor-beta (TGF-beta) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).</strong> J. Biol. Chem. 287: 8584-8597, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22275377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22275377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22275377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.341958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22275377">Canaff et al. (2012)</a> identified a heterozygous G-to-A transition in intron 3 of the MEN1 gene. Patient lymphoblastoid cells showed a wildtype transcript as well as an aberrant transcript with an in-frame deletion of 35 amino acids (184_218). In vitro studies and studies in patient cells showed that the mutant transcript was expressed and able to mediate the normal inhibition of the activity of some transcriptional regulators, including JunD (<a href="/entry/165162">165162</a>). However, it was defective in mediating TGF-beta (<a href="/entry/190180">190180</a>)-stimulated Smad3 (<a href="/entry/603109">603109</a>) tumor suppressor activity. Patient lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-beta than cells from an unaffected family member. <a href="#9" class="mim-tip-reference" title="Canaff, L., Vanbellinghen, J.-F., Kaji, H., Goltzman, D., Hendy, G. N. <strong>Impaired transforming growth factor-beta (TGF-beta) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).</strong> J. Biol. Chem. 287: 8584-8597, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22275377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22275377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22275377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.341958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22275377">Canaff et al. (2012)</a> concluded that this mutant menin isoform causes loss of control of cell proliferation via the selective loss of the TGF-beta signaling pathway, contributing to the development of MEN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22275377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<strong>Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.</strong>
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Cell 96: 143-152, 1999.
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[<a href="https://doi.org/10.1016/s0092-8674(00)80967-8" target="_blank">Full Text</a>]
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Agarwal, S. K., Kester, M. B., Debelenko, L. V., Heppner, C., Emmert-Buck, M. R., Skarulis, M. C., Doppman, J. L., Kim, Y. S., Lubensky, I. A., Zhuang, Z., Green, J. S., Guru, S. C., Manickam, P., Olufemi, S.-E., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J.
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[<a href="https://doi.org/10.1093/hmg/6.7.1169" target="_blank">Full Text</a>]
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<a id="Aoki1997" class="mim-anchor"></a>
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Aoki, A., Tsukada, T., Yasuda, H., Kayashima, S., Nagase, T., Ito, T., Suzuki, T., Matsukuma, S., Kuwabara, N., Yoshimoto, K., Yamaguchi, K.
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<strong>Multiple endocrine neoplasia type 1 presented with manic-depressive disorder: a case report with an identified MEN1 gene mutation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9438006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9438006</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9438006" 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/jjco/27.6.419" target="_blank">Full Text</a>]
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Balogh, K., Patocs, A., Majnik, J., Varga, F., Illyes, G., Hunyady, L., Racz, K.
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<strong>Unusual presentation of multiple endocrine neoplasia type 1 in a young woman with a novel mutation of the MEN1 gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15205994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15205994</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15205994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bassett, J. H. D., Forbes, S. A., Pannett, A. A. J., Lloyd, S. E., Christie, P. T., Wooding, C., Harding, B., Besser, G. M., Edwards, C. R., Monson, J. P., Sampson, J., Wass, J. A. H., Wheeler, M. H., Thakker, R. V.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463336</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9463336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/301729" target="_blank">Full Text</a>]
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Bear, J. C., Briones-Urbina, R., Fahey, J. F., Farid, N. R.
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<strong>Variant multiple endocrine neoplasia I (MEN I-Burin): further studies and non-linkage to HLA.</strong>
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Hum. Hered. 35: 15-20, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2857681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2857681</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2857681" 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/10.1159/000153508" target="_blank">Full Text</a>]
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Boni, R., Vortmeyer, A. O., Pack, S., Park, W.-S., Burg, G., Hofbauer, G., Darling, T., Liotta, L., Zhuang, Z.
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<strong>Somatic mutations of the MEN1 tumor suppressor gene detected in sporadic angiofibromas. (Letter)</strong>
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J. Invest. Derm. 111: 539-540, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9740255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9740255</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9740255" 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/10.1046/j.1523-1747.1998.00317.x" target="_blank">Full Text</a>]
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Busygina, V., Suphapeetiporn, K., Marek, L. R., Stowers, R. S., Xu, T., Bale, A. E.
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<strong>Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.</strong>
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Hum. Molec. Genet. 13: 2399-2408, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333582</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15333582" 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/ddh271" target="_blank">Full Text</a>]
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Canaff, L., Vanbellinghen, J.-F., Kaji, H., Goltzman, D., Hendy, G. N.
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<strong>Impaired transforming growth factor-beta (TGF-beta) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).</strong>
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J. Biol. Chem. 287: 8584-8597, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22275377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22275377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22275377[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=22275377" 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/10.1074/jbc.M112.341958" target="_blank">Full Text</a>]
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Carling, T., Correa, P., Hessman, O., Hedberg, J., Skogseid, B., Lindberg, D., Rastad, J., Westin, G., Akerstrom, G.
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<strong>Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism.</strong>
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J. Clin. Endocr. Metab. 83: 2960-2963, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9709976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9709976</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.83.8.4977" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200336" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.83.8.4846" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/mend.15.10.0717" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.95.4.1630" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0897-375" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.1.5388" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1200609" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.061358098" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.2.5506" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/6.7.1177" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2018.08.031" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:4<264::AID-HUMU2>3.0.CO;2-V" target="_blank">Full Text</a>]
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Sato, K., Obara, T., Yamazaki, K., Kanbe, M., Nakajima, K., Yamada, A., Yanagisawa, T., Kato, Y., Nishikawa, T., Takano, K.
|
|
<strong>Somatic mutations of the MEN1 gene and microsatellite instability in a case of tertiary hyperparathyroidism occurring during high phosphate therapy for acquired, hypophosphatemic osteomalacia.</strong>
|
|
J. Clin. Endocr. Metab. 86: 5564-5571, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11701736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11701736</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11701736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.86.11.7978" target="_blank">Full Text</a>]
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<a id="43" class="mim-anchor"></a>
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<a id="Schulte1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schulte, K.-M., Heinze, M., Mengel, M., Simon, D., Scheuring, S., Kohrer, K., Roher, H.-D.
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<strong>MEN I gene mutations in sporadic adrenal adenomas.</strong>
|
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Hum. Genet. 105: 603-610, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647896</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004399900193" target="_blank">Full Text</a>]
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<a id="44" class="mim-anchor"></a>
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<a id="Stratakis2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stratakis, C. A., Schussheim, D. H., Freedman, S. M., Keil, M. F., Pack, S. D., Agarwal, S. K., Skarulis, M. C., Weil, R. J., Lubensky, I. A., Zhuang, Z., Oldfield, E. H., Marx, S. J.
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<strong>Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1.</strong>
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J. Clin. Endocr. Metab. 85: 4776-4780, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134142</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11134142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.85.12.7064" target="_blank">Full Text</a>]
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<a id="45" class="mim-anchor"></a>
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<a id="Tahara2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tahara, H., Imanishi, Y., Yamada, T., Tsujimoto, Y., Tabata, T., Inoue, T., Inaba, M., Morii, H., Nishizawa, Y.
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<strong>Rare somatic inactivation of the multiple endocrine neoplasia type 1 gene in secondary hyperparathyroidism of uremia.</strong>
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J. Clin. Endocr. Metab. 85: 4113-4117, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11095441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11095441</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11095441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.85.11.6950" target="_blank">Full Text</a>]
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<a id="46" class="mim-anchor"></a>
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<a id="Teh1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E.
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<strong>A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)</strong>
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Am. J. Hum. Genet. 63: 1544-1549, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792884</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302097" target="_blank">Full Text</a>]
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<a id="Teh1998" class="mim-anchor"></a>
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Teh, B. T., Kytola, S., Farnebo, F., Bergman, L., Wong, F. K., Weber, G., Hayward, N., Larsson, C., Skogseid, B., Beckers, A., Phelan, C., Edwards, M., and 29 others.
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<strong>Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.</strong>
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J. Clin. Endocr. Metab. 83: 2621-2626, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9709921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9709921</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.83.8.5059" target="_blank">Full Text</a>]
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<a id="Turner2002" class="mim-anchor"></a>
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Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V.
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<strong>Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.</strong>
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J. Clin. Endocr. Metab. 87: 2688-2693, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050235</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank">Full Text</a>]
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<a id="49" class="mim-anchor"></a>
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<a id="Vortmeyer1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vortmeyer, A. O., Boni, R., Pak, E., Pack, S., Zhuang, Z.
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<strong>Multiple endocrine neoplasia 1 gene alterations in MEN1-associated and sporadic lipomas. (Letter)</strong>
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J. Nat. Cancer Inst. 90: 398-399, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9498491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9498491</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9498491" 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/jnci/90.5.398" target="_blank">Full Text</a>]
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Wautot, V., Vercherat, C., Lespinasse, J., Chambe, B., Lenoir, G. M., Zhang, C. X., Porchet, N., Cordier, M., Beroud, C., Calender, A.
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<strong>Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein.</strong>
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Hum. Mutat. 20: 35-47, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112656</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10092" target="_blank">Full Text</a>]
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<a id="Yokoyama2005" class="mim-anchor"></a>
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Yokoyama, A., Somervaille, T. C. P., Smith, K. S., Rozenblatt-Rosen, O., Meyerson, M., Cleary, M. L.
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<strong>The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.</strong>
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Cell 123: 207-218, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239140</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2005.09.025" target="_blank">Full Text</a>]
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<a id="Zablewska2003" class="mim-anchor"></a>
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Zablewska, B., Bylund, L., Mandic, S. A., Fromaget, M., Gaudray, P., Weber, G.
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<strong>Transcription regulation of the multiple endocrine neoplasia type 1 gene in human and mouse.</strong>
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J. Clin. Endocr. Metab. 88: 3845-3851, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915678</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2003-030288" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott - updated : 12/23/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/31/2012<br>Ada Hamosh - updated : 3/13/2012<br>Ada Hamosh - updated : 6/6/2011
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini : 2/7/2011
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 09/24/2022
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carol : 12/23/2021<br>carol : 01/31/2020<br>carol : 01/30/2020<br>carol : 02/28/2017<br>carol : 02/22/2017<br>carol : 02/21/2017<br>terry : 11/28/2012<br>carol : 11/6/2012<br>ckniffin : 10/31/2012<br>alopez : 3/14/2012<br>terry : 3/13/2012<br>alopez : 6/14/2011<br>terry : 6/6/2011<br>carol : 2/9/2011<br>terry : 2/9/2011<br>carol : 2/8/2011
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<strong>*</strong> 613733
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<h3>
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MENIN 1 ; MEN1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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MEN1 GENE<br />
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MENIN
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<strong><em>HGNC Approved Gene Symbol: MEN1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 254627002, 30664006, 786037006;
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<strong>ICD10CM:</strong> E31.21;
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<strong>ICD9CM:</strong> 258.01;
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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: 11q13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:64,803,516-64,811,294 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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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="6">
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<span class="mim-font">
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11q13.1
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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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Adrenal adenoma, somatic
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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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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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Angiofibroma, somatic
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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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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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Carcinoid tumor of lung
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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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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3
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|
</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Lipoma, somatic
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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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</span>
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</td>
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<td>
|
|
<span class="mim-font">
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</span>
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</td>
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|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Multiple endocrine neoplasia 1
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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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131100
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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>
|
|
<span class="mim-font">
|
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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|
Parathyroid adenoma, somatic
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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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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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>Description</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 MEN1 gene encodes menin, a nuclear scaffold protein that regulates gene transcription by coordinating chromatin remodeling. Menin interacts with several transcription factors, including JUND (165162), NFKB (164011), and SMAD3 (603109). MEN1 is considered to act as a tumor suppressor gene (summary by Canaff et al., 2012). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Chandrasekharappa et al. (1997) identified several candidate genes within the multiple endocrine neoplasia type I (MEN1; 131100) minimal interval on chromosome 11q13. One of the genes (MEN1) was found to encode a deduced 610-amino acid protein, which the authors designated menin. Northern blot analysis revealed ubiquitous expression of a 2.8-kb MEN1 transcript. </p><p>To identify additional candidate genes in the segment of less than 300 kb where the MEN1 locus is situated, Lemmens et al. (1997) used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes they identified, which they called SCG2 (suppressor candidate gene-2), proved to be identical to the MEN1 gene reported by Chandrasekharappa et al. (1997). The SCG2 transcript was 2.9 kb in all tissues studied, with an additional 4.2-kb transcript also being present in the pancreas and thymus. A human SCG2 cDNA clone, covering 2.3 kb at the 3-prime end of the gene, was isolated by hybridization screening. Northern blot analysis with this human sequence gave results identical to those from the bovine sequence. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</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>Chandrasekharappa et al. (1997) determined that the MEN1 gene contains 10 exons. </p>
|
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</span>
|
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<div>
|
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<br />
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</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>Chandrasekharappa et al. (1997) identified the MEN1 gene on chromosome 11q13. </p>
|
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</span>
|
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<div>
|
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<br />
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
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</span>
|
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</h4>
|
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</div>
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|
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|
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<span class="mim-text-font">
|
|
<p>Based on immunofluorescence, Western blotting of subcellular fractions, and epitope tagging with enhanced green fluorescent protein, Guru et al. (1998) demonstrated that menin is located primarily in the nucleus. They identified at least 2 independent nuclear localizations signals (NLSs), both located in the C-terminal fourth of the protein. They pointed out that among the 68 then-known independent disease-associated mutations, none of the 22 missense and 3 in-frame deletions affected either of the putative NLS sequences. However, if expressed, none of the truncated menin proteins resulting from the 43 known frameshift/nonsense mutations would retain both the NLSs. </p><p>Using a yeast 2-hybrid screen with menin as the bait, Agarwal et al. (1999) identified the transcription factor JunD (165162) as a direct menin-interacting partner. Menin did not interact directly with other Jun and Fos family members. The menin-JunD interaction was confirmed in vitro and in vivo. Menin repressed transcriptional activation mediated by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive reporter, or by JunD from an AP1-responsive reporter. Several naturally occurring and clustered MEN1 missense mutations disrupted menin interaction with JunD. These observations suggest that the tumor suppressor function of menin involves direct binding to JunD and inhibition of JunD-activated transcription. </p><p>Kaji et al. (2001) showed that menin inactivation by antisense RNA antagonizes transforming growth factor-beta (TGFB; 190180)-mediated cell growth inhibition. Menin interacts with SMAD3 (603109), and antisense menin suppresses TGFB-induced and SMAD3-induced transcriptional activity by inhibiting SMAD3/4-DNA binding at specific transcriptional regulatory sites. These results implicated a mechanism of tumorigenesis by menin inactivation. </p><p>To investigate how menin expression is regulated in both man and mouse, Zablewska et al. (2003) assayed a greater than 1 kb region upstream of the second exon of the MEN1 gene for promoter activity in luciferase reporter vectors. The basic promoter was located closely upstream of the most commonly expressed first exon. The region further upstream modified the activity. Repetitive elements of the short interspersed/Alu type covered the entire human upstream regulatory region and were the only apparent motif in common with its murine ortholog. They found that overexpression of menin in an inducible cell culture system downregulated the proximal promoter. In response to downregulation of MEN1 expression by RNA interference, the regulatory region activated the promoter in a compensatory manner. They concluded that their data confirmed that the expression of the MEN1 gene is regulated by feedback from its product menin. </p><p>To explore telomerase regulation, Lin and Elledge (2003) employed a general genetic screen in HeLa cells to identify negative regulators of TERT (187270). They discovered 3 tumor suppressor/oncogene pathways involved in TERT repression, including menin, which is a direct repressor of TERT. Depleting menin immortalized primary human fibroblasts and caused a transformation phenotype when coupled with expression of simian virus 40 large and small T antigen and oncogenic RAS (190020). </p><p>Human ML-2 leukemia cells lack a normal MLL (159555) gene and exclusively express an MLL/AF6 (MLLT4; 159559) fusion protein. Yokoyama et al. (2005) showed that MLL/AF6 associated with menin (MEN1) in ML-2 cells. Chromatin immunoprecipitation analysis showed both proteins present on upstream sites of the HOXA7 (142950), HOXA9 (142956), and HOXA10 (142957) promoters. Deletions and point mutations performed in the MLL portion of the MLL/ENL (MLLT1; 159556) fusion protein revealed a high affinity menin-binding motif (RXRFP) near the N-terminus. Interaction between oncogenic MLL and menin was required for initiation of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin was essential to maintain MLL-associated myeloid transformation. Acute genetic ablation of menin in mice reversed aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes and specifically abrogated differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Huang et al. (2012) reported the crystal structures of human menin in its free form and in complexes with MLL1 (159555) or with JUND (165162), or with an MLL1-LEDGF (603620) heterodimer. These structures showed that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1. </p>
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</span>
|
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Multiple Endocrine Neoplasia Type I</em></strong></p><p>
|
|
Chandrasekharappa et al. (1997) identified mutations in the MEN1 gene (613733.0001-613733.0012) in 14 probands from 15 families with multiple endocrine neoplasia type I. Twelve different heterozygous mutations were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism. </p><p>By mutation analysis of the SCG2 in 10 unrelated families with multiple endocrine neoplasia type I, Lemmens et al. (1997) identified 1 polymorphism and 9 different heterozygous mutations (1 missense, 4 nonsense, 1 insertional, and 3 deletional frameshifts) that segregated with the disease, thus providing confirmation for the identification of the MEN1 gene. </p><p>Giraud et al. (1998) studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families. </p><p>Teh et al. (1998) performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (613733.0032) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed. </p><p>In Spain, Cebrian et al. (1999) studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype. </p><p>The observation of loss of heterozygosity involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. Pannett and Thakker (2001) searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis. </p><p>By exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, Wautot et al. (2002) identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (165162), SMAD3, and nuclear factor kappa-B (NFKB1; 164011), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype. </p><p>Turner et al. (2002) ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (613733.0024). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (613733.0025), 209-211 (613733.0026), 418 (613733.0027), and 516 (613733.0028) accounts for 36.6% of all mutations. </p><p>In 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene (613733.0030). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. </p><p>Park et al. (2003) investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma. </p><p><strong><em>Familial Isolated Primary Hyperparathyroidism, MEN1 Variant</em></strong></p><p>
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|
In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism, Teh et al. (1998) found that affected members had a germline missense mutation in the MEN1 gene (613733.0020). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1 (131100). The pattern of transmission was autosomal dominant with high penetrance, as in MEN1. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. </p><p>In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas, Fujimori et al. (1998) identified a missense mutation in the MEN1 gene (613733.0021). </p><p><strong><em>Somatic Mutations in the MEN1 Gene</em></strong></p><p>
|
|
Heppner et al. (1997) found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (613733.0013) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). Heppner et al. (1997) suggested that many of these tumors likewise may have MEN1 somatic mutations. </p><p>Carling et al. (1998) used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (168450) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism. </p><p>Farnebo et al. (1998) screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors. </p><p>Prezant et al. (1998) screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis. </p><p>Heppner et al. (1999) studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH. </p><p>To investigate the role of the MEN1 gene in sporadic lipomas, Vortmeyer et al. (1998) analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (613733.0017). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient. </p><p>To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, Kjellman et al. (1999) screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity (LOH). The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (160980) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome. </p><p>Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. Gisselsson et al. (1999) analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in 4 cases also in the ostensibly normal homologs, resulting in homozygous loss of several loci. Among these, the MEN1 gene was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all 5 cases, adding to previous evidence for a second tumor suppressor locus in 11q13. </p><p>Tahara et al. (2000) analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, 608455; D11S4946; and D11S449), and for mutations of the MEN1-coding exons by PCR-based SSCP analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion in MEN1. They inferred that this mutation would result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathologic characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited. </p><p>Sato et al. (2001) reported a male patient with adult-onset, hypophosphatemic osteomalacia who had been treated with 1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary hyperparathyroidism developed. Sequence analysis of the coding exons of the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic parathyroid glands, accompanied by loss of heterozygosity at the 11q13 locus in 1 gland. These findings suggested that the repeated increase in serum phosphate concentrations for a prolonged period may be related to tumorigenesis of the parathyroid gland. </p><p>Jiao et al. (2011) explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death domain-associated protein, 603186) and ATRX (300032). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. Jiao et al. (2011) also found mutations in genes in the mTOR (601231) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To examine the role of MEN1 in tumor formation, Crabtree et al. (2001) generated a mouse model through homologous recombination of the mouse homolog Men1. Homozygous null mice died in utero at embryonic days 11.5 to 12.5, whereas heterozygous mice developed features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets showed a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas were frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary were seen by 16 months. All of the tumors tested showed loss of the wildtype Men1 allele, further supporting the role of MEN1 as a tumor suppressor gene. </p><p>Busygina et al. (2004) generated a null allele of Mnn1, the Drosophila homolog of the MEN1 gene, and showed that homozygous inactivation resulted in morphologically normal flies that are hypersensitive to ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and cisplatinum). The spectrum of agents to which mutant flies were sensitive and analysis of the molecular mechanisms of this sensitivity suggested a defect in nucleotide excision repair. Drosophila Mnn1 mutants had an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats (LATS1; 603473), which is a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Busygina et al. (2004) concluded that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA1 (113705) and MSH2 (609309) genes. </p><p>To examine the potential role of Men1 in hematopoiesis, Chen et al. (2006) targeted Men1 excision in a temporally-controlled manner. Disruption of Men1 in mice after birth gradually led to decreased total white blood cell count but did not significantly reduce red blood cell numbers. There was also reduced Hoxa9 (142956) expression and reduced colony formation by hematopoietic progenitors. Chen et al. (2006) determined that Men1 directly activated Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitated the methylation of histone H3 on lysine-4 (H3K4), and recruited the methylated H3K4-binding protein Chd1 (602118) to the locus. </p><p>In addition to cancer risk, MEN1 patients have been reported to have neurologic symptoms, including depression (MDD; 608516) (Aoki et al., 1997). Leng et al. (2018) studied a mouse model of MEN1 loss of function and demonstrated that menin deficiency increased Nfkb (164011)-induced Il1b (147720) levels in astroglia of male mice subjected to mild stress and lipopolysaccharide (LPS) injections. Whereas germline knockout mice died shortly after birth, a brain-specific knockout for Men1 was viable, had reduced Men1 astroglial expression, and showed depressive-like behaviors such as reduced mobility and impaired sociability. When animals were treated with an Nfkb inhibitor or an Il1b receptor antagonist, the depressive phenotype was rescued. Leng et al. (2018) also genotyped a human cohort of 1,032 MDD patients and identified one SNP (rs375804228) with an odds ratio of 3.2. Transfection studies of this variant, a G503D substitution in exon 10, in HEK293T cells showed reduced p65 (RELA; 164014) DNA binding. Leng et al. (2018) concluded that astroglial menin deficiency or mutation is able to produce neuroinflammation contributing to MDD. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>35 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 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, LEU22ARG
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<br />
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SNP: rs104894256,
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ClinVar: RCV000018157, RCV000182402
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a proband with multiple endocrine neoplasia type I (MEN1; 131100), Chandrasekharappa et al. (1997) identified a heterozygous missense mutation in the MEN1 gene, changing residue 22 from leucine to arginine (L22R). </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 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, 4-BP DEL, NT357
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<br />
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SNP: rs587776841,
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ClinVar: RCV000018173, RCV000182434, RCV000206170, RCV000491114
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous deletion of 4 bp starting from nucleotide 357 in the MEN1 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>.0003 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, 1-BP DEL, 416C
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<br />
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SNP: rs794728639,
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ClinVar: RCV000018159, RCV000182435, RCV000491671
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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 probands from 2 families with MEN1 (131100) not known to be related, Chandrasekharappa et al. (1997) identified a heterozygous 1-bp deletion of nucleotide 416, a cytidine, in the MEN1 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>.0004 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, 3-BP DEL, LYS119DEL
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<br />
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SNP: rs794728657,
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ClinVar: RCV000018160, RCV000182460, RCV000491280
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous 3-bp deletion in the MEN1 gene, resulting in deletion of lys119. </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 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, 1-BP DEL, 512C
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<br />
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SNP: rs397515385,
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gnomAD: rs397515385,
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ClinVar: RCV000018161, RCV000182436, RCV000491332
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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 probands with MEN1 (131100) from families not known to be related, Chandrasekharappa et al. (1997) identified a heterozygous deletion of nucleotide 512, a cytidine, in the MEN1 gene. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
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MEN1, TRP198TER
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|
<br />
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|
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SNP: rs104894257, rs104894258,
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|
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ClinVar: RCV000018162
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous missense mutation in the MEN1 gene, converting codon 198 from tryptophan to stop. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
MEN1, 4-BP DEL, NT735
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|
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|
|
<br />
|
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|
|
SNP: rs794728640,
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|
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ClinVar: RCV000018163, RCV000182437, RCV000491752
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous deletion of 4 bp in the MEN1 gene, starting from nucleotide position 735. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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MEN1, 1-BP DEL, 1132G
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<br />
|
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|
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SNP: rs1555164986,
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ClinVar: RCV000509058
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous deletion of nucleotide 1132, a guanine, in the MEN1 gene. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, 3-BP DEL, GLU363DEL
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<br />
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|
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SNP: rs869025185,
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|
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ClinVar: RCV000018165, RCV000255250, RCV000491660
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous 3-bp deletion in the MEN1 gene, resulting in deletion of glu363. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, TRP436ARG
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<br />
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SNP: rs104894259,
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|
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ClinVar: RCV000018166, RCV000255755, RCV004018639
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous missense mutation in the MEN1 gene, converting codon 436 from tryptophan to arginine (W436R). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, TRP436TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894260,
|
|
|
|
|
|
|
|
ClinVar: RCV000018167, RCV000518947
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation in the MEN1 gene, converting codon 436 from tryptophan to stop (W436X). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, ARG527TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894261,
|
|
|
|
|
|
|
|
ClinVar: RCV000018168, RCV000182423, RCV000491431, RCV004813043
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation at codon 527 of the MEN1 gene, converting arginine to stop (R527X). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PARATHYROID ADENOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, GLU26LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28931612,
|
|
|
|
|
|
|
|
ClinVar: RCV000018169, RCV000490040, RCV000817082
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 1 in 2,000. Heppner et al. (1997) stated that in more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as MEN1. In most cases, however, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal. Approximately 30% of sporadic parathyroid tumors show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumor suppressor gene. Among 33 sporadic parathyroid tumors (see 131100), Heppner et al. (1997) found a somatic MEN1 gene mutation in 7 (21%), while the corresponding MEN1 germline sequence was normal in each patient. All tumors with MEN1 gene mutations showed LOH on 11q13, making the tumor cells hemi- or homozygous for the mutant allele. They concluded that somatic MEN1 gene mutations contribute to tumorigenesis in a substantial number of parathyroid tumors not associated with the MEN1 syndrome, thus fulfilling the characteristics of the Knudson model. In 1 of the 7 cases with a somatic cell mutation, a GAG-to-AAG change was found in codon 26 (E26K). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, GLN260TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894266,
|
|
|
|
|
|
|
|
ClinVar: RCV000018170, RCV000491298, RCV004748527, RCV004998100
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of MEN1 (131100), Agarwal et al. (1997) identified a heterozygous nonsense mutation in the MEN1 gene, converting glutamine-260 to stop (Q260X). The patient had multiple tumors of the parathyroid glands, Zollinger-Ellison syndrome, and growth hormone-prolactin macroadenoma of the anterior pituitary gland. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CARCINOID TUMOR OF LUNG</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, 1-BP INS, 1650C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs767319284,
|
|
|
|
|
|
gnomAD: rs767319284,
|
|
|
|
|
|
ClinVar: RCV000018171, RCV000269197, RCV000491230, RCV000548407
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lung carcinoids occur sporadically and rarely in association with MEN1 (see 131100). Debelenko et al. (1997) studied 11 sporadic lung carcinoids for LOH in 1 locus and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from an MEN1 patient was studied. In 4 of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All 4 tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1-bp insertion (1650insC) , a 1-bp deletion, a 13-bp deletion, and a single nucleotide substitution affecting a donor splice site. Each mutation predicted truncation or potentially complete loss of MEN1. The remaining 7 tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at 11q13 and a complex germline MEN1 gene mutation. The findings of this study represented the first defined genetic alteration in carcinoids. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, ARG460TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894267,
|
|
|
|
|
|
|
|
ClinVar: RCV000018172, RCV000129526, RCV000182421
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Olufemi et al. (1998) demonstrated an arg460-to-ter mutation (R460X) in the MEN1 gene in affected members of 4 families with MEN1 (131100), originally described by Farid et al. (1980) and Bear et al. (1985). Affected members had prolactinomas, carcinoid tumors of the lung and thymus, and hyperparathyroidism. The disorder was called the MEN1 Burin variant by Bear et al. (1985). All 4 families lived in the Burin peninsula of Newfoundland. The ancestors of each of the 4 independently identified families came from a group of very small, isolated, now-abandoned communities within a 20-mile radius on the north shore of Fortune Bay. No single common ancestor was identified by examination of genealogic records, but there were common surnames in the earliest generations recorded. By haplotype analysis, Olufemi et al. (1998) demonstrated a common haplotype over a 2.5-Mb region that was shared by affected members of all 4 families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 LIPOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, 4-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000018173, RCV000182434, RCV000206170, RCV000491114
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of sporadic lipoma (see 131100), Vortmeyer et al. (1998) identified deletion of TGTC from exon 2 of the MEN1 gene. The deletion was not found in constitutional DNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ANGIOFIBROMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, LYS135ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913034,
|
|
|
|
|
|
|
|
ClinVar: RCV000018174
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Angiofibromas are benign cutaneous tumors that can occur sporadically or as multiple lesions in association with inherited diseases. As a rule, multiple facial angiofibromas are thought to be specific for tuberous sclerosis (see 191100); however, Darling et al. (1997) showed that angiofibromas may also be associated with multiple endocrine neoplasia type I. Boni et al. (1998) investigated whether the MEN1 gene might be implicated in sporadic angiofibromas. For this purpose, they analyzed 19 sporadic facial angiofibromas (see 131100) for mutation in the MEN1 gene using PCR-based SSCP and sequencing analysis. All patients had a negative family history for tuberous sclerosis and MEN1 disease. Aberrant bands were detected in 2 tumors: one mutation was an A-to-T transversion at nucleotide 517 changing codon 135 from AAG (lys) to TAG (ile); the second mutation was a transversion of GG to AA at nucleotides 1184 and 1185 resulting in a change of codon 358 from GAG (glu) to GAA (also glu) and codon 359 from GAG (glu) to AAG (lys) (613733.0019). The mutations were in exons 2 and 8, respectively. The mutations were observed only in tumor DNA and not in normal control tissue. LOH analysis, performed using 2 polymorphic markers flanking the MEN1 gene, showed no LOH in any of the 19 angiofibromas, including the 2 displaying mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 ANGIOFIBROMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, 1184GG-AA, GLU359LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607234,
|
|
|
|
|
|
|
|
ClinVar: RCV000018175
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 613733.0018 and Boni et al. (1998). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY, MEN1 VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, GLU255LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894268,
|
|
|
|
|
|
|
|
ClinVar: RCV000018176, RCV001753420
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Caucasian English family in which 7 family members from 2 generations had primary hyperparathyroidism, Teh et al. (1998) found that affected members had a germline missense mutation in codon 255 (GAG to AAG) of exon 4, causing an amino acid change from glutamic acid to lysine (glu255 to lys). The G-to-A transition at nucleotide 763 of the cDNA also gave rise to a HindIII restriction cleavage site for the mutant allele. This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1 (131100). The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY, MEN1 VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, VAL184GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894262,
|
|
|
|
|
|
|
|
ClinVar: RCV000018177
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas (see MEN1, 131100), Fujimori et al. (1998) demonstrated a T-to-A transversion at codon 184 in exon 3, predicted to result in an amino acid change from valine to glutamic acid (V184E). (Fujimori et al. (1998) incorrectly described the nucleotide change as a transition and the amino acid change as valine to glutamine. The change was presumably GTG (val) to GAG (glu); this was confirmed by Fujimori (1999).) </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 ADRENAL ADENOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, THR552SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913035,
|
|
|
|
|
|
|
|
ClinVar: RCV000018178
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Because loss of heterozygosity on 11q13 occurs in about 20% of sporadic adrenal neoplasms, and adrenal lesions, mostly benign, occur in up to 40% of patients from MEN1 kindreds, MEN1 was considered a prime candidate gene in these lesions. Schulte et al. (1999) studied 15 patients with sporadic adrenal adenoma (see 131100) and 1 patient with multinodular hyperplasia. Of the 16 patients, 4 had incidentally discovered masses ('incidentalomas'), 5 had Conn syndrome, 6 had Cushing syndrome (219080), and 9 had high sex hormone production. Schulte et al. (1999) performed direct DNA sequencing of the menin gene in 14 sporadic adrenal adenomas and 1 case of adrenal hyperplasia. They identified 1 heterozygous missense mutation, thr552 to ser, in a hormonally inactive adrenal adenoma. This is another example of mutation in the MEN1 gene causing a sporadic form of tumors that occur as part of MEN1 disease. Other examples include parathyroid adenoma, gastrinoma, and bronchial carcinoid tumors. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, HIS139ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894263,
|
|
|
|
|
|
|
|
ClinVar: RCV000018179, RCV000491226, RCV004998101
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Stratakis et al. (2000) reported a 2.3-cm pituitary macroadenoma in a 5-year-old boy with familial MEN1 (131100). He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. Germline DNA of the propositus and his affected relatives had a heterozygous point mutation in the MEN1 gene that led to a his139-to-asp substitution. The patient had no other detectable germline mutations in either MEN1 allele. DNA sequencing and FISH with a MEN1 genomic DNA sequence probe each demonstrated 1 copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 'second hit' as a tumor cause. The authors stated that this patient represents the earliest presentation of any morbid endocrine tumor in MEN1. </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>.0024 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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MEN1, IVS4, G-A, -9
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|
<br />
|
|
|
|
SNP: rs794728625,
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|
|
ClinVar: RCV000182415, RCV000205749, RCV002408796
|
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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 7 unrelated families with MEN1 (131100), Turner et al. (2002) found a G-to-A transition at nucleotide 5168 in intron 4 of the MEN1 gene, which resulted in a novel acceptor splice site in intron 4. Use of this novel acceptor site leads to incorporation of the 7 bp 5-prime to the naturally occurring acceptor splice site, with resultant frameshift and premature termination. </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>.0025 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
MEN1, 3-BP DEL, 2641GAA
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<br />
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|
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ClinVar: RCV000018160, RCV000182460, RCV000491280
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|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a 3-bp in-frame deletion of GAA at codon 118-119 of the MEN1 gene. Turner et al. (2002) noted that this mutation had been reported in 8 other MEN1 families; this mutation had been recorded by Bassett et al. (1998). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</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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MEN1, 4-BP DEL, 4480CAGT
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<br />
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SNP: rs1941851693,
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ClinVar: RCV000018182
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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 affected members of a family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a 4-bp deletion involving codons 209 to 211 in exon 3 of the MEN1 gene. The mutation was predicted to result in frameshift and premature termination after 11 amino acids. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
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MEN1, ASP418ASN
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<br />
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|
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SNP: rs104894264,
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ClinVar: RCV000018183, RCV000490854, RCV001269702
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 families with MEN1 (131100), Turner et al. (2002) found a heterozygous G-to-A transition at nucleotide 7262 in exon 9 of the MEN1 gene, resulting in an asp418-to-asn (D418N) amino acid change. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
MEN1, 1-BP DEL, 7773C
|
|
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|
|
<br />
|
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|
|
SNP: rs767319284,
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|
|
gnomAD: rs767319284,
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|
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|
|
ClinVar: RCV000182439, RCV000228926, RCV001012050
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a deletion of a C nucleotide at position 7773 in exon 10 of the MEN1 gene, resulting in a frameshift and premature termination 42 amino acids after codon 516. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, CYS354TER
|
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|
|
<br />
|
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|
|
SNP: rs104894265,
|
|
|
|
|
|
|
|
ClinVar: RCV000018185
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with MEN1 (131100), Balogh et al. (2004) identified a heterozygous C-to-A transversion in exon 8 of the MEN1 gene, resulting in a cys354-to-ter (C354X) mutation. The woman was first investigated at the age of 25 years for abdominal discomfort and left upper abdominal pain. A giant pancreatic tumor was identified by abdominal ultrasonography and CT scan. The diagnosis of a clinically nonfunctioning pancreatic neuroendocrine tumor was established by clinical studies, and the patient underwent a distal pancreatectomy. Histology proved a well-differentiated multinodular neuroendocrine tumor of the pancreas. During surgery, a subcutaneous lipoma was removed from the abdominal wall. Two days later, the patient developed primary hyperparathyroidism, and 2 enlarged parathyroid glands were surgically removed. Her family history was unremarkable, except for an unknown disorder in her father that had caused an early death. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, 6-BP INS, NT879
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555165485,
|
|
|
|
|
|
|
|
ClinVar: RCV000632129
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a Japanese family with MEN1 (131100) and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene, 878insCTGCAG (insertion of 6 nucleotides after nucleotide 878), resulting in the insertion of 2 amino acids, leu-gln, after amino acid 256 of the menin protein (256insLQ). The authors noted that CTGCAG is a palindromic sequence, repeated twice in the wildtype allele from nucleotides 879 to 890. Okamoto et al. (2002) found a significant difference (p = 0.0022) on chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas, and suggested that there may be a correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, IVS9, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863223311,
|
|
|
|
|
|
|
|
ClinVar: RCV000018187, RCV002381254, RCV003517126
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Chilean family with familial isolated primary hyperparathyroidism (FIHP; 145000), Carrasco et al. (2004) identified a heterozygous G-to-A transition at nucleotide 7361 of the tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9+1G-A). All 11 family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and wildtype sequences. RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. The authors concluded that this mutation produces an aberrant splicing of mRNA that could lead to a truncated protein without activity, explaining the clinical picture of this patient and his family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, 12-BP DEL, NT1466
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs760199250,
|
|
|
|
|
|
|
|
ClinVar: RCV000018188
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Among 19 Finnish MEN1 (131100) probands, Teh et al. (1998) identified a heterozygous 1466del12 mutation in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. </p><p>Ebeling et al. (2004) used church records and MEN1 family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 and 1657insC (613733.0033). They traced the roots of 8 families with the 1466del12 mutation to a small village approximately 45 kilometers east of Oulu, where the founder couple were born in 1705 and 1709, respectively. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, 1-BP INS, 1657C
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000018171, RCV000269197, RCV000491230, RCV000548407
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ebeling et al. (2004) used church records and MEN1 (131100) family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 (613733.0032) and 1657insC. Four families with the 1657incC mutation could be traced back to a couple living 200 kilometers northeast of Oulu born in 1844 and 1846, and not farther than only 4 generations from the youngest. The authors noted that while the most prevalent mutation (1466del12; 613733.0032) is a unique Finnish mutation, the 1657delC mutation seems to be a hotspot, as it has been found in 5 different MEN1 populations (Guo and Sawicki, 2001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, IVS5, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1060499976,
|
|
|
|
|
|
|
|
ClinVar: RCV000018190, RCV002426511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Frank-Raue et al. (2005) reported a family with coexistence of a mutation in the MEN1 gene, resulting in multiple endocrine neoplasia with recurrent hyperparathyroidism (131100) , and in the RET gene (Y791F; 164761.0034), which alone produced no clinical phenotype and carries a low risk of medullary thyroid carcinoma, also implicating a low incidence of pheochromocytoma and primary hyperparathyroidism. A heterozygous substitution of G to A at position +1 in intron 5 of the MEN1 gene disrupted the consensus sequence in the splice donor site. This was predicted to lead to a nonsense peptide sequence from this position and premature termination of protein synthesis. Two patients carrying both mutations had typical manifestations of MEN1; the third patient carrying both mutations, being 6 years of age at the time of the report, showed no clinical manifestations. The authors concluded that the 2 mutations do not interact. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 MULTIPLE ENDOCRINE NEOPLASIA, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEN1, IVS3DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs794728622,
|
|
|
|
|
|
|
|
ClinVar: RCV000032982, RCV002362604, RCV002510773
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation family with MEN1 (131100), Canaff et al. (2012) identified a heterozygous G-to-A transition in intron 3 of the MEN1 gene. Patient lymphoblastoid cells showed a wildtype transcript as well as an aberrant transcript with an in-frame deletion of 35 amino acids (184_218). In vitro studies and studies in patient cells showed that the mutant transcript was expressed and able to mediate the normal inhibition of the activity of some transcriptional regulators, including JunD (165162). However, it was defective in mediating TGF-beta (190180)-stimulated Smad3 (603109) tumor suppressor activity. Patient lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-beta than cells from an unaffected family member. Canaff et al. (2012) concluded that this mutant menin isoform causes loss of control of cell proliferation via the selective loss of the TGF-beta signaling pathway, contributing to the development of MEN1. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
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|
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|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Agarwal, S. K., Guru, S. C., Heppner, C., Erdos, M. R., Collins, R. M., Park, S. Y., Saggar, S., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Marx, S. J., Burns, A. L.
|
|
<strong>Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.</strong>
|
|
Cell 96: 143-152, 1999.
|
|
|
|
|
|
[PubMed: 9989505]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(00)80967-8]
|
|
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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