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Entry
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- *155541 - MELANOCORTIN 4 RECEPTOR; MC4R
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- OMIM
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</form>
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<div id="mimAlertBanner">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*155541</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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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/155541">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000166603;t=ENST00000299766" 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=4160" 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=155541" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000166603;t=ENST00000299766" 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_005912" 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_005912" 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=155541" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01116&isoform_id=01116_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/MC4R" 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/291978,998457,29824916,46575765,60392672,75516817,85567086,117553554,117553556,117553558,117553560,119508433,119583509,189054300,409684074,409684076,409684078,409684080,409684082,2316779153,2316779155,2316779157" 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/P32245" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4160" 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=ENSG00000166603;t=ENST00000299766" 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=MC4R" 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=MC4R" 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+4160" 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/MC4R" 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:4160" 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/4160" 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=chr18&hgg_gene=ENST00000299766.5&hgg_start=60371062&hgg_end=60372775&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=155541[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=155541[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MC4R/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000166603" 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=MC4R" 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=MC4R" 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=MC4R" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MC4R&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/PA30676" 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:6932" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:99457" 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/MC4R#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:99457" 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/4160/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002217/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4160" 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-021223-2" 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>
|
|
</div>
|
|
</div>
|
|
|
|
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:155541" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
|
|
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|
</div>
|
|
</div>
|
|
</div>
|
|
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|
|
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|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<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>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<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:4160" 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=MC4R&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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|
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</div>
|
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|
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<span>
|
|
<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>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
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<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
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</div>
|
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<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
155541
|
|
</span>
|
|
</span>
|
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</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
MELANOCORTIN 4 RECEPTOR; MC4R
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|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MCR RECEPTOR
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</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=MC4R" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MC4R</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/18/220?start=-3&limit=10&highlight=220">18q21.32</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:60371062-60372775&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'})">18:60,371,062-60,372,775</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/18/220?start=-3&limit=10&highlight=220">
|
|
18q21.32
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Obesity, resistance to (BMIQ20)}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618406"> 618406 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Obesity (BMIQ20)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618406"> 618406 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
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<p><a href="#12" class="mim-tip-reference" title="Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S. J., DelValle, J., Yamada, T. <strong>Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.</strong> J. Biol. Chem. 268: 15174-15179, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392067</a>]" pmid="8392067">Gantz et al. (1993)</a> cloned a fourth member of the melanocortin receptor family of 7-transmembrane G-protein linked receptors. By Northern blot analysis and in situ hybridization, the melanocortin-4 receptor (MC4R) was found to be expressed primarily in the brain; its expression was notably absent in the adrenal cortex, melanocytes, and placenta. The profile of responses of MC4R, transfected into COS-1 cells and L cells, to different melanocortins distinguished it from the previously described melanocortin receptors. (See <a href="/entry/155555">155555</a>, <a href="/entry/202200">202200</a>, and <a href="/entry/155540">155540</a>.) MC4R is a 333-amino acid protein encoded by a single exon (<a href="#53" class="mim-tip-reference" title="Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., O'Rahilly, S. <strong>A frameshift mutation in MC4R associated with dominantly inherited human obesity.</strong> Nature Genet. 20: 111-112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771698</a>] [<a href="https://doi.org/10.1038/2404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771698">Yeo et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8392067+9771698" 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>By means of fluorescence chromosomal in situ hybridization, <a href="#12" class="mim-tip-reference" title="Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S. J., DelValle, J., Yamada, T. <strong>Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.</strong> J. Biol. Chem. 268: 15174-15179, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392067</a>]" pmid="8392067">Gantz et al. (1993)</a> localized the MC4R gene to chromosome 18q21.3. By fluorescence in situ hybridization (FISH), <a href="#36" class="mim-tip-reference" title="Magenis, R. E., Smith, L., Nadeau, J. H., Johnson, K. R., Mountjoy, K. G., Cone, R. D. <strong>Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human.</strong> Mammalian Genome 5: 503-508, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7949735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7949735</a>] [<a href="https://doi.org/10.1007/BF00369320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7949735">Magenis et al. (1994)</a> mapped the MC4R gene to 18q22. Using FISH and radiation hybrid mapping, <a href="#46" class="mim-tip-reference" title="Sundaramurthy, D., Campbell, D. A., Leek, J. P., Markham, A. F., Pieri, L. F. <strong>Assignment of the melanocortin 4 receptor (MC4R) gene to human chromosome band 18q22 by in situ hybridisation and radiation hybrid mapping.</strong> Cytogenet. Cell Genet. 82: 97-98, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9763669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9763669</a>] [<a href="https://doi.org/10.1159/000015074" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9763669">Sundaramurthy et al. (1998)</a> localized the MC4R gene to 18q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8392067+9763669+7949735" 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>Nonsense-mediated decay (NMD) inhibits the accumulation of nonsense- or frameshift-mutated mRNA and thus minimizes the synthesis of truncated proteins with potential dominant-negative effects. <a href="#3" class="mim-tip-reference" title="Brocke, K. S., Neu-Yilik, G., Gehring, N. H., Hentze, M. W., Kulozik, A. E. <strong>The human intronless melanocortin 4-receptor gene is NMD insensitive.</strong> Hum. Molec. Genet. 11: 331-335, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823452</a>] [<a href="https://doi.org/10.1093/hmg/11.3.331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823452">Brocke et al. (2002)</a> investigated the NMD sensitivity of nonsense-mutated transcripts of MC4R. Nonsense-mutated variants of MC4R transcripts were stable and expressed truncated proteins that were detectable in the lysates of transfected cells. The authors hypothesized that the lack of necessity for splicing in the naturally intronless MC4R gene may allow it to escape from NMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823452" 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 using a combination of pharmacologic, molecular genetic, electrophysiologic, and feeding studies, <a href="#39" class="mim-tip-reference" title="Mineur, Y. S., Abizaid, A., Rao, Y., Salas, R., DiLeone, R. J., Gundisch, D., Diano, S., De Biasi, M., Horvath, T. L., Gao, X.-B., Picciotto, M. R. <strong>Nicotine decreases food intake through activation of POMC neurons.</strong> Science 332: 1330-1332, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21659607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21659607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21659607[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/10.1126/science.1201889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21659607">Mineur et al. (2011)</a> found that activation of hypothalamic alpha-3 (<a href="/entry/118503">118503</a>)-beta-4 (<a href="/entry/118509">118509</a>) nicotinic acetylcholine receptors leads to activation of proopiomelanocortin (POMC; <a href="/entry/176830">176830</a>) neurons. POMC neurons and subsequent activation of melanocortin-4 receptors were critical for nicotinic-induced decreases in food intake in mice. The study of <a href="#39" class="mim-tip-reference" title="Mineur, Y. S., Abizaid, A., Rao, Y., Salas, R., DiLeone, R. J., Gundisch, D., Diano, S., De Biasi, M., Horvath, T. L., Gao, X.-B., Picciotto, M. R. <strong>Nicotine decreases food intake through activation of POMC neurons.</strong> Science 332: 1330-1332, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21659607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21659607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21659607[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/10.1126/science.1201889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21659607">Mineur et al. (2011)</a> demonstrated that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identified critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21659607" 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="Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., Malenka, R. C. <strong>Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.</strong> Nature 487: 183-189, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22785313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22785313</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22785313[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/nature11160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22785313">Lim et al. (2012)</a> showed that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor (DRD1; <a href="/entry/126449">126449</a>)-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin-4 receptor. Stress-elicited increases in behavioral measurements of anhedonia, but not increases in measurements of behavioral despair, are prevented by blocking these melanocortin-4 receptor-mediated synaptic changes in vivo. <a href="#29" class="mim-tip-reference" title="Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., Malenka, R. C. <strong>Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.</strong> Nature 487: 183-189, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22785313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22785313</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22785313[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/nature11160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22785313">Lim et al. (2012)</a> concluded that stress-elicited anhedonia requires a neuropeptide-triggered, cell type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22785313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#14" class="mim-tip-reference" title="Ghamari-Langroudi, M., Digby, G. J., Sebag, J. A., Millhauser, G. L., Palomino, R., Matthews, R., Gillyard, T., Panaro, B. L., Tough, I. R., Cox, H. M., Denton, J. S., Cone, R. D. <strong>G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.</strong> Nature 520: 94-98, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25600267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25600267</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25600267[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/nature14051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25600267">Ghamari-Langroudi et al. (2015)</a> showed that regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by alpha-melanocyte-stimulating hormone (alpha-MSH; see <a href="/entry/176830">176830</a>) and Agouti-related protein (AGRP; <a href="/entry/602311">602311</a>) can be mediated independently of G-alpha-s (see <a href="/entry/139320">139320</a>) signaling by ligand-induced coupling of Mc4r to closure of inwardly rectifying potassium channel Kir7.1 (<a href="/entry/603208">603208</a>). Furthermore, Agrp is a biased agonist that hyperpolarizes neurons by binding to Mc4r and opening Kir7.1, independently of its inhibition of alpha-Msh binding. Consequently, Kir7.1 signaling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of Mc4r to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signaling, including the gene dosage effect of Mc4r and the sustained effects of Agrp on food intake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25600267" 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>Through molecular and genetic analyses in mice, <a href="#40" class="mim-tip-reference" title="Mosialou, I., Shikhel, S., Liu, J.-M., Maurizi, A., Luo, N., He, Z., Huang, Y., Zong, H., Friedman, R. A., Barasch, J., Lanzano, P., Deng, L., Leibel, R. L., Rubin, M., Nickolas, T., Chung, W., Zeltser, L. M., Williams, K. W., Pessin, J. E., Kousteni, S. <strong>MC4R-dependent suppression of appetite by bone-derived lipocalin-2.</strong> Nature 543: 385-390, 2017. Note: Erratum: Nature 546: 440 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28273060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28273060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28273060[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/nature21697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28273060">Mosialou et al. (2017)</a> identified lipocalin-2 (LCN2; <a href="/entry/600181">600181</a>) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrated that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived Lcn2 inhibits food intake. Lcn2 crosses the blood-brain barrier, binds to Mc4r in the paraventricular and ventromedial neurons of the hypothalamus, and activates an Mc4r-dependent anorexigenic (appetite-suppressing) pathway. <a href="#40" class="mim-tip-reference" title="Mosialou, I., Shikhel, S., Liu, J.-M., Maurizi, A., Luo, N., He, Z., Huang, Y., Zong, H., Friedman, R. A., Barasch, J., Lanzano, P., Deng, L., Leibel, R. L., Rubin, M., Nickolas, T., Chung, W., Zeltser, L. M., Williams, K. W., Pessin, J. E., Kousteni, S. <strong>MC4R-dependent suppression of appetite by bone-derived lipocalin-2.</strong> Nature 543: 385-390, 2017. Note: Erratum: Nature 546: 440 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28273060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28273060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28273060[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/nature21697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28273060">Mosialou et al. (2017)</a> concluded that their results identified Lcn2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and showed that the control of appetite is an endocrine function of bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28273060" 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="#43" class="mim-tip-reference" title="Siljee, J. E., Wang, Y., Bernard, A. A., Ersoy, B. A., Zhang, S., Marley, A., Von Zastrow, M., Reiter, J. F., Vaisse, C. <strong>Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity.</strong> Nature Genet. 50: 180-185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29311635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29311635</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29311635[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/s41588-017-0020-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29311635">Siljee et al. (2018)</a> noted that MC4R localizes to the cell membrane when expressed in unciliated heterologous cells. However, they found that human MC4R with a C-terminal GFP tag localized to primary cilia in ciliated cells in vitro. Using a transgenic mouse line, the authors confirmed that Sim1 (<a href="/entry/603128">603128</a>)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN) were ciliated. Confocal imaging of the PVN of knockin mice expressing MC4R-GFP demonstrated that MC4R colocalized with Adcy3 (<a href="/entry/600291">600291</a>) at primary cilia of a subset of PVN neurons in vivo. Human MC4R with obesity (<a href="/entry/618406">618406</a>)-associated mutations in the third intracellular domain had significantly decreased ciliary localization when expressed in mouse IMCD3 cells. In vivo analysis using transgenic mice revealed that one of the MC4R mutant proteins failed to colocalize with Adcy3 at primary cilia, suggesting that localization of MC4R to primary cilia is essential for its function. Inhibition of Adcy3 at primary cilia of Mc4r-expressing neurons of mice increased their food intake and was sufficient to cause obesity compared with controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29311635" 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="#55" class="mim-tip-reference" title="Yu, J., Gimenez, L. E., Hernandez, C. C., Wu, Y., Wein, A. H., Han, G. W., McClary, K., Mittal, S. R., Burdsall, K., Stauch, B., Wu, L., Stevens, S. N., Peisley, A., Williams, S. Y., Chen, V., Millhauser, G. L., Zhao, S., Cone, R. D., Stevens, R. C. <strong>Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding.</strong> Science 368: 428-433, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32327598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32327598</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32327598[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/10.1126/science.aaz8995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32327598">Yu et al. (2020)</a> reported the crystal structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca(2+) was identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca(2+) increased the affinity and potency of the endogenous agonist alpha-melanocyte-stimulating hormone (alpha-MSH; see POMC, <a href="/entry/176830">176830</a>) at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1 (KCNJ13; <a href="/entry/603208">603208</a>), while lacking cAMP stimulation, highlighted a heterotrimeric GTP-binding protein-independent mechanism for this signaling modality. <a href="#55" class="mim-tip-reference" title="Yu, J., Gimenez, L. E., Hernandez, C. C., Wu, Y., Wein, A. H., Han, G. W., McClary, K., Mittal, S. R., Burdsall, K., Stauch, B., Wu, L., Stevens, S. N., Peisley, A., Williams, S. Y., Chen, V., Millhauser, G. L., Zhao, S., Cone, R. D., Stevens, R. C. <strong>Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding.</strong> Science 368: 428-433, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32327598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32327598</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32327598[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/10.1126/science.aaz8995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32327598">Yu et al. (2020)</a> concluded that MC4R is a structurally divergent G protein-coupled receptor (GPCR) with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32327598" 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="#53" class="mim-tip-reference" title="Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., O'Rahilly, S. <strong>A frameshift mutation in MC4R associated with dominantly inherited human obesity.</strong> Nature Genet. 20: 111-112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771698</a>] [<a href="https://doi.org/10.1038/2404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771698">Yeo et al. (1998)</a> and <a href="#48" class="mim-tip-reference" title="Vaisse, C., Clement, K., Guy-Grand, B., Froguel, P. <strong>A frameshift mutation in human MC4R is associated with a dominant form of obesity.</strong> Nature Genet 20: 113-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771699</a>] [<a href="https://doi.org/10.1038/2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771699">Vaisse et al. (1998)</a> described a severely obese (BMIQ20; <a href="/entry/618406">618406</a>) child and adult, respectively, with heterozygous mutations in the MC4R gene: a 4-bp deletion (<a href="#0001">155541.0001</a>) in the child and a 4-bp insertion (<a href="#0002">155541.0002</a>) in the adult. The mutations segregated with obesity in both families in a pattern consistent with autosomal dominant inheritance. Molecular abnormalities have been identified in autosomal recessive severe obesity involving the leptin gene (<a href="/entry/164160#0001">164160.0001</a>), the leptin receptor gene (<a href="/entry/601007#0002">601007.0002</a>), the prohormone convertase-1 gene (PC1; <a href="/entry/162150#0001">162150.0001</a>), and the proopiomelanocortin gene (POMC; <a href="/entry/176830#0001">176830.0001</a>). Hypogonadotropic hypogonadism is found in association with mutations in the leptin, leptin receptor, and PC1 genes, and hypoadrenalism is found with POMC and PC1 gene mutations; short stature is associated with mutations in the leptin receptor gene. There was no evidence of impaired adrenal function in the MC4R-deficient subjects; sexual development and fertility were normal, and affected subjects were tall, which was of interest given the increased linear growth exhibited by heterozygous Mc4r-deficient mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9771699+9771698" 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 SSCP, <a href="#24" class="mim-tip-reference" title="Hinney, A., Schmidt, A., Nottebom, K., Heibult, O., Becker, I., Ziegler, A., Gerber, G., Sina, M., Gorg, T., Mayer, H., Siegfried, W., Fichter, M., Remschmidt, H., Hebebrand, J. <strong>Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.</strong> J. Clin. Endocr. Metab. 84: 1483-1486, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199800</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199800">Hinney et al. (1999)</a> screened the coding region of the MC4R gene in 306 extremely obese children and adolescents, 25 healthy underweight students, 52 normal weight individuals, 51 inpatients with anorexia nervosa (<a href="/entry/606788">606788</a>), and 27 patients with bulimia nervosa (<a href="/entry/607499">607499</a>). Several mutations were identified, including a 4-bp deletion (<a href="#0001">155541.0001</a>) that resulted in a frameshift, yielding a truncated protein. This mutation had been assumed to be associated with dominantly inherited morbid obesity in humans. Both the index patient (body mass index (BMI), 42.06 kg/m2; height, 171 cm; age, 19.6 years) and her mother (BMI, 37.55 kg/m2; height, 164 cm; age, 42.5 years) were heterozygous for this deletion. A tyr35-to-ter substitution (<a href="#0003">155541.0003</a>) was detected in 2 obese probands (BMI, 31.29 kg/m2 and 45.91 kg/m2, respectively); this mutation led to a truncated protein that encompassed the N-terminal extracellular domain. Both carriers also showed an asp37-to-val mutation in cis. In both cases these mutations were transmitted from their obese mothers, indicating they form a haplotype. A male obese proband harbored 2 missense mutations, and 4 different missense mutations were detected in 4 different male probands. All mutations in the MC4R gene were found only in extremely obese individuals whose BMIs were all greater than the 99th percentile. An ile251-to-leu (I251L) polymorphism was found in similar frequencies in all groups studied. The authors concluded that MC4R mutations are not uncommon. While the data supported dominantly inherited obesity because of the 3 obese probands with haploinsufficiency, the functional significance of the missense mutations remained to be determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199800" 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="#44" class="mim-tip-reference" title="Sina, M., Hinney, A., Ziegler, A., Neupert, T., Mayer, H., Siegfried, W., Blum, W. F., Remschmidt, H., Hebebrand, J. <strong>Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene.</strong> Am. J. Hum. Genet. 65: 1501-1507, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577903[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302660" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577903">Sina et al. (1999)</a> extended the MC4R mutation screen to another 186 extremely obese children and adolescents and identified an additional haploinsufficiency carrier, bringing the total number of mutation-carrying obese patients identified to 4. They genotyped and phenotyped 43 family members of these 4 index patients. A total of 19 mutation carriers were identified. Extreme obesity was the predominating phenotype; however, moderate obesity occurred in 3 of the carriers. No other specific phenotypic abnormalities were detected. Female haploinsufficiency carriers were heavier than male carriers in the respective families, a finding similar to findings in Mc4r-knockout mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577903" 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="Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J.-P., Guy-Grand, B., Tounian, P. <strong>Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.</strong> J. Pediat. 139: 204-209, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487744</a>] [<a href="https://doi.org/10.1067/mpd.2001.116284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487744">Dubern et al. (2001)</a> identified heterozygous missense MC4R mutations (<a href="#0005">155541.0005</a>-<a href="#0008">155541.0008</a>) in 4 of 63 unrelated children with severe obesity. The same mutation was not found in any of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. <a href="#10" class="mim-tip-reference" title="Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J.-P., Guy-Grand, B., Tounian, P. <strong>Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.</strong> J. Pediat. 139: 204-209, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487744</a>] [<a href="https://doi.org/10.1067/mpd.2001.116284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487744">Dubern et al. (2001)</a> concluded that MC4R mutations may be a nonnegligible cause of severe obesity in children with variable expression and penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Jacobson, P., Ukkola, O., Rankinen, T., Snyder, E. E., Leon, A. S., Rao, D. C., Skinner, J. S., Wilmore, J. H., Lonn, L., Cowan, G. S., Jr., Sjostrom, L., Bouchard, C. <strong>Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish obese subjects, the HERITAGE family study, and a Memphis cohort.</strong> J. Clin. Endocr. Metab. 87: 4442-4446, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12364415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12364415</a>] [<a href="https://doi.org/10.1210/jc.2002-020568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12364415">Jacobson et al. (2002)</a> determined the prevalence of mutations in the coding and flanking regions of the MC4R gene in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family study, and a Memphis cohort. A total of 433 white and 95 black subjects (94% females) were screened for mutations by direct sequencing. Three previously described missense variants and 9 novel (3 missense, 6 silent) variants were detected. None of them showed significant association with obesity or related phenotypes. In addition, 2 novel deletions were found in 2 heterozygous obese women which were predicted to encode a truncated nonfunctional receptor. No pathogenic mutations were found among obese blacks or nonobese controls. Furthermore, none of the null mutations found in other populations was present in this sample. The authors concluded that their results do not support the prevailing notion that sequence variation in the MC4R gene is a frequent cause of human obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12364415" 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="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> stated that MC4R deficiency is the most common form of monogenic obesity. To define the clinical spectrum, mode of inheritance, genotype-phenotype correlations, and pathophysiologic mechanisms leading to obesity, they determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. In 29 probands (5.8%), they found mutations in MC4R (see, e.g., <a href="#0010">155541.0010</a>-<a href="#0019">155541.0019</a>); 23 were heterozygotes and 6 were homozygotes. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual signaling capacity had a less severe phenotype. Thus, MC4R mutations are inherited in a codominant manner. The correlation between the signaling properties of these mutant receptors and energy intake emphasized the key role of this receptor in the control of eating behavior. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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 means of transient transfection in vitro, <a href="#54" class="mim-tip-reference" title="Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., O'Rahilly, S. <strong>Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.</strong> Hum. Molec. Genet. 12: 561-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588803</a>] [<a href="https://doi.org/10.1093/hmg/ddg057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588803">Yeo et al. (2003)</a> examined the functional properties of 12 different mutations in human MC4R that result in severe, familial, early-onset obesity. Of the 9 missense mutants studied, 4 (including <a href="#0013">155541.0013</a>, <a href="#0014">155541.0014</a>, and <a href="#0018">155541.0018</a>) were completely unable to generate cAMP in response to ligand and 5 were partially impaired. Four (including <a href="#0014">155541.0014</a> and <a href="#0017">155541.0017</a>) showed impaired cell surface expression and 6 showed reduced ligand binding. The mutant protein I316S (<a href="#0016">155541.0016</a>) showed reduced affinity for alpha-MSH but retained normal affinity for the antagonist agouti-related protein (AGRP; <a href="/entry/602311">602311</a>). None of the mutations inhibited signaling through cotransfected wildtype receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588803" 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 cohort of 172 patients presenting with severe childhood obesity and a family history of obesity, <a href="#34" class="mim-tip-reference" title="Lubrano-Berthelier, C., Durand, E., Dubern, B., Shapiro, A., Dazin, P., Weill, J., Ferron, C., Froguel, P., Vaisse, C. <strong>Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations.</strong> Hum. Molec. Genet. 12: 145-153, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499395</a>] [<a href="https://doi.org/10.1093/hmg/ddg016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499395">Lubrano-Berthelier et al. (2003)</a> screened for mutations in the coding region of the MC4R gene and identified 3 heterozygous MC4R mutations in 3 patients. A functional analysis of 14 MC4R mutations, including the 3 identified in this study, indicated that all mutations altered the activation of the receptor by the endogenous agonist alpha-MSH (see <a href="/entry/176830">176830</a>). <a href="#34" class="mim-tip-reference" title="Lubrano-Berthelier, C., Durand, E., Dubern, B., Shapiro, A., Dazin, P., Weill, J., Ferron, C., Froguel, P., Vaisse, C. <strong>Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations.</strong> Hum. Molec. Genet. 12: 145-153, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499395</a>] [<a href="https://doi.org/10.1093/hmg/ddg016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499395">Lubrano-Berthelier et al. (2003)</a> further demonstrated that greater than 80% of childhood obesity-associated heterozygous MC4R mutations led to intracellular retention of the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Branson, R., Potoczna, N., Kral, J. G., Lentes, K.-U., Hoehe, M. R., Horber, F. F. <strong>Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.</strong> New Eng. J. Med. 348: 1096-1103, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646666</a>] [<a href="https://doi.org/10.1056/NEJMoa021971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646666">Branson et al. (2003)</a> sequenced the complete MC4R coding region and the leptin-binding domain of the leptin receptor (LEPR; <a href="/entry/601007">601007</a>) in 469 severely obese white subjects (370 women and 99 men). Normal-weight controls were 15 women and 10 men without a history of dieting or a family history of obesity. MC4R mutations, including 5 novel variants, were found in 24 obese subjects (5.1%) and 1 control (4%). Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and BMI with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2% of obese subjects without mutations and none of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha-MSH, the ligand of MC4R. <a href="#30" class="mim-tip-reference" title="List, J. F., Habener, J. F. <strong>Defective melanocortin 4 receptors in hyperphagia and morbid obesity. (Editorial)</strong> New Eng. J. Med. 348: 1160-1163, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646673</a>] [<a href="https://doi.org/10.1056/NEJMe030013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646673">List and Habener (2003)</a> commented on the possible importance of ethnic background in the frequency of mutations in MC4R in obesity. They also suggested that the findings of <a href="#2" class="mim-tip-reference" title="Branson, R., Potoczna, N., Kral, J. G., Lentes, K.-U., Hoehe, M. R., Horber, F. F. <strong>Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.</strong> New Eng. J. Med. 348: 1096-1103, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646666</a>] [<a href="https://doi.org/10.1056/NEJMoa021971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646666">Branson et al. (2003)</a> be interpreted with caution, as they differed from earlier findings of a binge-eating disorder prevalence of 5% among carriers of MC4R mutations (<a href="#44" class="mim-tip-reference" title="Sina, M., Hinney, A., Ziegler, A., Neupert, T., Mayer, H., Siegfried, W., Blum, W. F., Remschmidt, H., Hebebrand, J. <strong>Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene.</strong> Am. J. Hum. Genet. 65: 1501-1507, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577903[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302660" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577903">Sina et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12646673+12646666+10577903" 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 detailed pharmacologic studies of 11 different missense mutations in the MC4R gene associated with obesity, <a href="#41" class="mim-tip-reference" title="Nijenhuis, W. A. J., Garner, K. M., van Rozen, R. J., Adan, R. A. H. <strong>Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity.</strong> J. Biol. Chem. 278: 22939-22945, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690102</a>] [<a href="https://doi.org/10.1074/jbc.M211326200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690102">Nijenhuis et al. (2003)</a> found that all the mutant receptors were poorly expressed at the cell surface and showed a decreased maximal response to agonist, indicating that the mutations impair receptor function. The findings supported the hypothesis that loss of function of MC4R contributes to obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12690102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Hinney, A., Hohmann, S., Geller, F., Vogel, C., Hess, C., Wermter, A.-K., Brokamp, B., Goldschmidt, H., Siegfried, W., Remschmidt, H., Schafer, H., Gudermann, T., Hebebrand, J. <strong>Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity.</strong> J. Clin. Endocr. Metab. 88: 4258-4267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970296</a>] [<a href="https://doi.org/10.1210/jc.2003-030233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970296">Hinney et al. (2003)</a> performed a mutation screen of the coding region of the MC4R gene in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; 5 of these were novel. In vitro assays revealed that 9 of the 16 mutations led to impaired cAMP responses, compared with wildtype receptor constructs. The association test based on functionally relevant mutations was positive (p = 0.006, Fisher exact test, one-sided). They also screened a total of 1,040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (p = 0.033). The authors concluded that their results supported the hypothesis that these MC4R mutations represent major gene effects for obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12970296" 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="Santini, F., Maffei, M., Ceccarini, G., Pelosini, C., Scartabelli, G., Rosellini, V., Chiellini, C., Marsili, A., Lisi, S., Tonacchera, M., Agretti, P., Chiovato, L., Mammoli, C., Vitti, P., Pinchera, A. <strong>Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation.</strong> J. Clin. Endocr. Metab. 89: 904-908, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764812</a>] [<a href="https://doi.org/10.1210/jc.2003-031175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764812">Santini et al. (2004)</a> screened a population of Italian obese subjects for MC4R variants, demonstrating a 1.7% prevalence of potentially pathogenic mutations. They reported a novel heterozygous missense mutation that impaired MC4R functional activity in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764812" 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="#49" class="mim-tip-reference" title="Valli-Jaakola, K., Lipsanen-Nyman, M., Oksanen, L., Hollenberg, A. N., Kontula, K., Bjorbaek, C., Schalin-Jantti, C. <strong>Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults.</strong> J. Clin. Endocr. Metab. 89: 940-945, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764818</a>] [<a href="https://doi.org/10.1210/jc.2003-031182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764818">Valli-Jaakola et al. (2004)</a> screened 2 Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to 70% before age 10) and 252 morbidly obese adults (body mass index greater than 40 kg/m2) for MC4R mutations. They identified a pathogenic mutation (S127L; <a href="#0021">155541.0021</a>) in 1 child, causing severe early-onset obesity. They also identified a novel polymorphism in the coding region and 2 novel variations outside the coding region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764818" 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="#19" class="mim-tip-reference" title="Hebebrand, J., Geller, F., Dempfle, A., Heinzel-Gutenbrunner, M., Raab, M., Gerber, G., Wermter, A.-K., Horro, F. F., Blundell, J., Schafer, H., Remschmidt, H., Herpertz, S., Hinney, A. <strong>Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations.</strong> Molec. Psychiat. 9: 796-800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15037865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15037865</a>] [<a href="https://doi.org/10.1038/sj.mp.4001491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15037865">Hebebrand et al. (2004)</a> compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations to wildtype controls. No significant differences in binge-eating episodes between carriers of the MC4R variants and wildtype controls were detected, and <a href="#19" class="mim-tip-reference" title="Hebebrand, J., Geller, F., Dempfle, A., Heinzel-Gutenbrunner, M., Raab, M., Gerber, G., Wermter, A.-K., Horro, F. F., Blundell, J., Schafer, H., Remschmidt, H., Herpertz, S., Hinney, A. <strong>Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations.</strong> Molec. Psychiat. 9: 796-800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15037865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15037865</a>] [<a href="https://doi.org/10.1038/sj.mp.4001491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15037865">Hebebrand et al. (2004)</a> concluded that binge-eating episodes are not a distinct feature of MC4R mutation carriers. This analysis was different from the study of <a href="#2" class="mim-tip-reference" title="Branson, R., Potoczna, N., Kral, J. G., Lentes, K.-U., Hoehe, M. R., Horber, F. F. <strong>Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.</strong> New Eng. J. Med. 348: 1096-1103, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646666</a>] [<a href="https://doi.org/10.1056/NEJMoa021971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646666">Branson et al. (2003)</a> because <a href="#19" class="mim-tip-reference" title="Hebebrand, J., Geller, F., Dempfle, A., Heinzel-Gutenbrunner, M., Raab, M., Gerber, G., Wermter, A.-K., Horro, F. F., Blundell, J., Schafer, H., Remschmidt, H., Herpertz, S., Hinney, A. <strong>Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations.</strong> Molec. Psychiat. 9: 796-800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15037865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15037865</a>] [<a href="https://doi.org/10.1038/sj.mp.4001491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15037865">Hebebrand et al. (2004)</a> studied only carriers of mutations that had been shown to be of functional relevance in vitro and did not include carriers of silent variants in the open reading frame, variants in untranslated regions (UTRs), or the val103-to-ile (V103I; <a href="#0024">155541.0024</a>) or I251L polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12646666+15037865" 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 transmission/disequilibrium test on 520 trios with obesity, <a href="#13" class="mim-tip-reference" title="Geller, F., Reichwald, K., Dempfle, A., Illig, T., Vollmert, C., Herpertz, S., Siffert, W., Platzer, M., Hess, C., Gudermann, T., Biebermann, H., Wichmann, H.-E., Schafer, H., Hinney, A., Hebebrand, J. <strong>Melanocortin-4 receptor gene variant 1103 is negatively associated with obesity.</strong> Am. J. Hum. Genet. 74: 572-581, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14973783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14973783</a>] [<a href="https://doi.org/10.1086/382490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14973783">Geller et al. (2004)</a> unexpectedly observed a lower transmission rate of the 103I allele (p = 0.017) in the MC4R gene. Metaanalysis of combined data from 7,713 individuals demonstrated a negative association of the 103I allele with obesity (odds ratio, 0.69; p = 0.03). Noting the apparent protective effect against obesity, the authors suggested that variation in the MC4R gene might entail both loss and gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14973783" 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 linear regression analysis of data from 2 large German population-based surveys with a total of 7,937 participants, <a href="#20" class="mim-tip-reference" title="Heid, I. M., Vollmert, C., Hinney, A., Doring, A., Geller, F., Lowel, H., Wichmann, H.-E., Illig, T., Hebebrand, J., Kronenberg, F., the KORA group. <strong>Association of the 1031 MC4R allele with decreased body mass in 7937 participants of two population based surveys.</strong> J. Med. Genet. 42: e21, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805150</a>] [<a href="https://doi.org/10.1136/jmg.2004.027011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805150">Heid et al. (2005)</a> found a significant decrease of 0.52 BMI units (p = 0.043) for heterozygous carriers of the V103I variant, which was observed in 3.7% of participants. Logistic regression analysis yielded a significantly negative association of the MC4R variant with above-average weight (odds ratio, 0.75; p = 0.017). Similar results were obtained in a comparison of obese (BMI greater than 30) to nonobese participants of either sex (odds ratio, 0.69; p = 0.026). The authors concluded that the V103I polymorphism could be regarded as contributing to polygenetically regulated body weight. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805150" 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="#33" class="mim-tip-reference" title="Lubrano-Berthelier, C., Dubern, B., Lacorte, J.-M., Picard, F., Shapiro, A., Zhang, S., Bertrais, S., Hercberg, S., Basdevant, A., Clement, K., Vaisse, C. <strong>Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating.</strong> J. Clin. Endocr. Metab. 91: 1811-1818, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16507637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16507637</a>] [<a href="https://doi.org/10.1210/jc.2005-1411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16507637">Lubrano-Berthelier et al. (2006)</a> determined the prevalence of MC4R mutations in a cohort of severely obese adults and the clinical phenotype and the phenotype-genotype relationships of adult MC4R mutation carriers. The prevalence of obesity-specific MC4R mutations was 2.6% (95% CI = 1.5-3.7). The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%) and in patients with a later onset of the disease (2.35%). Adult obese MC4R mutation carriers did not present with binge eating or with any specific clinical phenotype. The authors concluded that the severity of the functional alterations of the mutated MC4Rs and, in particular, the intracellular retention of the receptor correlated with both the severity and the onset of obesity in the mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16507637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Hinney, A., Bettecken, T., Tarnow, P., Brumm, H., Reichwald, K., Lichtner, P., Scherag, A., Nguyen, T. T., Schlumberger, P., Rief, W., Vollmert, C., Illig, T., Wichmann, H.-E., Schafer, H., Platzer, M., Biebermann, H., Meitinger, T., Hebebrand, J. <strong>Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany.</strong> J. Clin. Endocr. Metab. 91: 1761-1769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16492696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16492696</a>] [<a href="https://doi.org/10.1210/jc.2005-2056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16492696">Hinney et al. (2006)</a> investigated the prevalence and spectrum of MC4R mutations in 4,068 individuals of a German population-based study group (KORA-S4) and 1,003 German obese adults (BMI greater than 30 kg/m2). Sixteen (6 novel) coding nonsynonymous mutations were detected in 27 heterozygous individuals of KORA-S4. Four of the mutation alleles led to impaired receptor function in vitro; however, none of these 6 heterozygous mutation carriers was obese. In the obese adults, 6 coding nonsynonymous and a nonsense mutation were detected in 13 individuals. Only the nonsense mutation allele entailed impaired receptor function. The authors concluded that individuals heterozygous for nonsynonymous MC4R mutation alleles entailing impaired function were not obese and that nonsynonymous MC4R mutations causing impaired receptor function were rare in German obese adults (2 in 1,003 = 0.2%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16492696" 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 direct sequencing of the coding region of the MC4R gene in a cohort of 289 Czech children and adolescents with early-onset obesity, <a href="#17" class="mim-tip-reference" title="Hainerova, I., Larsen, L. H., Holst, B., Finkova, M., Hainer, V., Lebl, J., Hansen, T. and Pedersen, O. <strong>Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis.</strong> J. Clin. Endocr. Metab. 92: 3689-3696, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17579204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17579204</a>] [<a href="https://doi.org/10.1210/jc.2007-0352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17579204">Hainerova et al. (2007)</a> found a prevalence of 2.4% of MC4R homozygous and heterozygous mutations. One novel variant (C84R) showed a significant reduction in cAMP signal properties of the MC4R. There was a similar response of MC4R mutation carriers and noncarriers to diet management. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17579204" 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 genomewide association study of 318,237 SNPs for insulin resistance and related phenotypes in 2,684 Indian Asians and 11,955 individuals of Indian Asian or European ancestry, <a href="#4" class="mim-tip-reference" title="Chambers, J. C., Elliott, P., Zabaneh, D., Zhang, W., Li, Y., Froguel, P., Balding, D., Scott, J., Kooner, J. S. <strong>Common genetic variation near MC4R is associated with waist circumference and insulin resistance.</strong> Nature Genet. 40: 716-718, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454146</a>] [<a href="https://doi.org/10.1038/ng.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454146">Chambers et al. (2008)</a> found association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12970134;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12970134</a>, located near the MC4R gene, and waist circumference (p = 1.7 x 10(-9)). Homozygotes for the risk allele had an approximately 2 cm greater waist circumference compared to wildtype. The authors concluded that genetic variation near MC4R is associated with a risk of adiposity and insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18454146" 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="Loos, R. J. F., Lindgren, C. M., Li, S., Wheeler, E., Zhao, J. H., Prokopenko, I., Inouye, M., Freathy, R. M., Attwood, A. P., Beckmann, J. S., Berndt, S. I., Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and 96 others. <strong>Common variants near MC4R are associated with fat mass, weight and risk of obesity.</strong> Nature Genet. 40: 768-775, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18454148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454148">Loos et al. (2008)</a> performed a metaanalysis of data from 4 European population-based studies and 3 disease-case series, involving a total of 16,876 individuals of European descent, and found a significant association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17782313;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17782313</a>, located 188 kb downstream of the MC4R gene, and BMI in adults (p = 2.8 x 10(-15)) and children (p = 1.5 x 10(-8)). In case-control analyses, the odds for severe childhood obesity reached 1.30 (p = 8.0 x 10(-11)), and overtransmission of the risk allele to obese offspring was observed in 660 families. The authors concluded that common variants near the MC4R gene influence fat mass, weight, and obesity risk at the population level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18454148" 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="#51" class="mim-tip-reference" title="Willer, C. J., Speliotes, E. K., Loos, R. J. F., Li, S., Lindgren, C. M., Heid, I. M., Berndt, S. I., Elliott, A. L., Jackson, A. U., Lamina, C., Lettre, G., Lim, N., and 134 others. <strong>Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.</strong> Nature Genet. 41: 25-34, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079261[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079261">Willer et al. (2009)</a> performed a metaanalysis of 15 genomewide association studies for BMI comprising 32,387 participants and followed up top signals in 14 additional cohorts comprising 59,082 participants. They strongly confirmed association with MC4R at SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17782313;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17782313</a> with a per-allele change in BMI of 0.20 and an overall P value of 1.1 x 10(-20). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19079261" 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="Hardy, R., Wills, A. K., Wong, A., Elks, C. E., Wareham, N. J., Loos, R. J. F., Kuh, D., Ong, K. K. <strong>Life course variations in the associations between FTO and MC4R gene variants and body size.</strong> Hum. Molec. Genet. 19: 545-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19880856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19880856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19880856[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/10.1093/hmg/ddp504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19880856">Hardy et al. (2010)</a> genotyped variants in FTO (<a href="/entry/610966">610966</a>; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9939609;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9939609</a>) and near MC4R (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17782313;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17782313</a>) in 1,240 men and 1,239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2-20 years) or adulthood (20-53 years). The association between FTO <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9939609;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9939609</a> and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; P less than 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele), and then weakened during adulthood (-0.003 SDS/A-allele/year, p = 0.001). MC4R <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17782313;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17782313</a> showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; p = 0.006), peaked at age 20 years (0.13 SDS/C-allele), and weakened during adulthood (-0.002 SDS/C-allele/year, p = 0.05). <a href="#18" class="mim-tip-reference" title="Hardy, R., Wills, A. K., Wong, A., Elks, C. E., Wareham, N. J., Loos, R. J. F., Kuh, D., Ong, K. K. <strong>Life course variations in the associations between FTO and MC4R gene variants and body size.</strong> Hum. Molec. Genet. 19: 545-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19880856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19880856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19880856[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/10.1093/hmg/ddp504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19880856">Hardy et al. (2010)</a> concluded that genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19880856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Drabkin, M., Birk, O. S., Birk, R. <strong>Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred.</strong> BMC Med. Genet. 19: 135, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30068297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30068297</a>] [<a href="https://doi.org/10.1186/s12881-018-0654-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30068297">Drabkin et al. (2018)</a> tested 16 members of a large consanguineous Bedouin family, including 4 with autosomal recessive early-onset obesity, and identified a novel mutation (c.124G-T, E42X) in the MC4R gene that eliminated nearly all functional domains of the protein. The phenotype in homozygotes in this family was much more severe than in heterozygotes for the mutation, both with regard to degree of obesity and metabolic consequences (e.g., triglycerides). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30068297" 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>It has been hypothesized that MC4R mutations found in association with obesity result in a loss of MC4R gene function due to haploinsufficiency. <a href="#6" class="mim-tip-reference" title="Cody, J. D., Reveles, X. T., Hale, D. E., Lehman, D., Coon, H., Leach, R. J. <strong>Haplosufficiency of the melanocortin-4 receptor gene in individuals with deletions of 18q.</strong> Hum. Genet. 105: 424-427, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10598807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10598807</a>] [<a href="https://doi.org/10.1007/s004390051125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10598807">Cody et al. (1999)</a> studied the molecular basis of the phenotype of individuals with large deletions of 18q. Because of its location at 18q21.3, the MC4R gene was hemizygous in approximately one-third of the individuals in this study. If hemizygosity of the MC4R gene results in haploinsufficiency-induced obesity, then individuals with deletion of 18q whose deletions included the MC4R gene should be obese in comparison with those individuals whose deletion did not include the gene. The data of <a href="#6" class="mim-tip-reference" title="Cody, J. D., Reveles, X. T., Hale, D. E., Lehman, D., Coon, H., Leach, R. J. <strong>Haplosufficiency of the melanocortin-4 receptor gene in individuals with deletions of 18q.</strong> Hum. Genet. 105: 424-427, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10598807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10598807</a>] [<a href="https://doi.org/10.1007/s004390051125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10598807">Cody et al. (1999)</a> indicated no difference in obesity among those deleted and not deleted for the gene. Thus, the MC4R gene product must be haplosufficient, and the involvement of MC4R in obesity may reflect a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10598807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Heisler, L. K., Cowley, M. A., Tecott, L. H., Fan, W., Low, M. J., Smart, J. L., Rubinstein, M., Tatro, J. B., Marcus, J. N., Holstege, H., Lee, C. E., Cone, R. D., Elmquist, J. K. <strong>Activation of central melanocortin pathways by fenfluramine.</strong> Science 297: 609-611, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12142539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12142539</a>] [<a href="https://doi.org/10.1126/science.1072327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12142539">Heisler et al. (2002)</a> found that genetic or pharmacologic blockade of MC4R and MC3R (<a href="/entry/155540">155540</a>) is sufficient to attenuate the anorectic efficacy of threshold doses of d-FEN (D-fenfluramine), suggesting that drugs targeting these downstream melanocortin pathways may act in part in a manner similar to d-FEN to decrease food intake and body weight with fewer side effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12142539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., Smith, F. J., Campfield, L. A., Burn, P., Lee, F. <strong>Targeted disruption of the melanocortin-4 receptor results in obesity in mice.</strong> Cell 88: 131-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9019399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9019399</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81865-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9019399">Huszar et al. (1997)</a> found that inactivation of the melanocortin-4 receptor by gene targeting in mice resulted in a maturity-onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycinemia. This syndrome recapitulated several of the characteristic features of the 'agouti' syndrome, which results from ectopic expression of agouti protein (<a href="/entry/600201">600201</a>), a pigmentation factor normally expressed in the skin. The findings identified a novel signaling pathway in the mouse for body weight regulation and supported a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the melanocortin-4 receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9019399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Marsh, D. J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K. A., Fisher, S. L., Burn, P., Palmiter, R. D. <strong>Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides.</strong> Nature Genet. 21: 119-122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916804</a>] [<a href="https://doi.org/10.1038/5070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916804">Marsh et al. (1999)</a> found that the leptin resistance of obese Mc4r -/- mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF; <a href="/entry/118945">118945</a>), corticotropin-releasing factor (CRF; <a href="/entry/122560">122560</a>), or urocortin (UCN; <a href="/entry/600945">600945</a>); or the orexigenic (appetite-stimulating) actions of neuropeptide Y (NPY; <a href="/entry/162640">162640</a>) or peptide YY (PYY; <a href="/entry/600781">600781</a>), indicating that these neuromodulators act independently or downstream of Mc4r signaling. <a href="#37" class="mim-tip-reference" title="Marsh, D. J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K. A., Fisher, S. L., Burn, P., Palmiter, R. D. <strong>Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides.</strong> Nature Genet. 21: 119-122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916804</a>] [<a href="https://doi.org/10.1038/5070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916804">Marsh et al. (1999)</a> showed that homozygous Mc4r-deficient mice do not respond to the anorectic action of a melanocyte-stimulating hormone (MSH)-like agonist, suggesting that alpha-MSH (see <a href="/entry/176830">176830</a>) inhibits feeding primarily by activating Mc4r. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9916804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Kim, K. S., Larsen, N., Short, T., Plastow, G., Rothschild, M. F. <strong>A missense variant of the porcine melanocortin-4 receptor (MC4R) gene is associated with fatness, growth, and feed intake traits.</strong> Mammalian Genome 11: 131-135, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10656927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10656927</a>] [<a href="https://doi.org/10.1007/s003350010025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10656927">Kim et al. (2000)</a> studied MC4R as a candidate gene for the control of economically important growth and performance traits in the pig. They found a missense mutation in a region highly conserved among melanocortin receptor genes: a G-to-A transition at a position corresponding to human codon 298, changing GAU (asp) to AAU (asn). The asp298 allele was associated with less backfat thickness, slower growth rate, and lower feed intake. In an association study of this MC4R polymorphism in a large number of individual animals from several different pig lines, they found a significant association of MC4R genotypes with backfat, growth rate, and feed intake in a number of lines. The authors considered it likely that the variant amino acid residue of the MC4R mutation (or a closely linked mutation) causes a significant change of the MC4R function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10656927" 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="#5" class="mim-tip-reference" title="Chen, A. S., Marsh, D. J., Trumbauer, M. E., Frazier, E. G., Guan, X.-M., Yu, H., Rosenblum, C. I., Vongs, A., Feng, Y., Cao, L., Metzger, J. M., Strack, A. M., and 9 others. <strong>Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.</strong> Nature Genet. 26: 97-102, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973258</a>] [<a href="https://doi.org/10.1038/79254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973258">Chen et al. (2000)</a> evaluated the potential role of MC3R in energy homeostasis by studying Mc3r-deficient (Mc3r -/-) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. Mice lacking both Mc3r and Mc4r became significantly heavier than Mc4r -/- mice. <a href="#5" class="mim-tip-reference" title="Chen, A. S., Marsh, D. J., Trumbauer, M. E., Frazier, E. G., Guan, X.-M., Yu, H., Rosenblum, C. I., Vongs, A., Feng, Y., Cao, L., Metzger, J. M., Strack, A. M., and 9 others. <strong>Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.</strong> Nature Genet. 26: 97-102, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973258</a>] [<a href="https://doi.org/10.1038/79254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973258">Chen et al. (2000)</a> concluded that Mc3r and Mc4r serve nonredundant roles in the regulation of energy homeostasis. <a href="#7" class="mim-tip-reference" title="Cummings, D. E., Schwartz, M. W. <strong>Melanocortins and body weight: a tale of two receptors.</strong> Nature Genet. 26: 8-9, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973234</a>] [<a href="https://doi.org/10.1038/79223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973234">Cummings and Schwartz (2000)</a> showed that these studies demonstrated that the 2 melanocortin receptor isoforms reduce body weight through distinct and complementary mechanisms. Mc4r regulates food intake and possibly energy expenditure, whereas Mc3r influences feed efficiency and the petitioning of fuel stores into fat. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10973234+10973258" 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="Ste Marie, L., Miura, G. I., Marsh, D. J., Yagaloff, K., Palmiter, R. D. <strong>A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.</strong> Proc. Nat. Acad. Sci. 97: 12339-12344, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027312</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11027312[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.220409497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11027312">Ste Marie et al. (2000)</a> studied Mc4r-null mice to determine whether aberrant metabolism contributes to their late-onset obesity. The consumption of the null mice was restricted to (i.e., pair-fed with) that of wildtype mice. The null females maintained body weights intermediate to those of wildtype and nonpair-fed null females, whereas pair-feeding normalized the body weights of null male mice. These and other findings indicated that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in Mc3r-null mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11027312" 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 a combination of genetic, pharmacologic, and anatomic approaches, <a href="#50" class="mim-tip-reference" title="Van der Ploeg, L. H. T., Martin, W. J., Howard, A. D., Nargund, R. P., Austin, C. P., Guan, X., Drisko, J., Cashen, D., Sebhat, I., Patchett, A. A., Figueroa, D. J., DiLella, A. G., and 22 others. <strong>A role for the melanocortin 4 receptor in sexual function.</strong> Proc. Nat. Acad. Sci. 99: 11381-11386, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12172010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12172010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12172010[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.172378699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12172010">Van der Ploeg et al. (2002)</a> showed that MC4R, implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence was based on several findings: a highly selective nonpeptide MC4R agonist augmented erectile activity initiated by electrical stimulation of the cavernous nerve in wildtype, but not Mc4r-null, mice; copulatory behavior was enhanced by administration of a selective MC4R agonist and was diminished in mice lacking Mc4r; RT-PCR- and non-PCR-based methods demonstrated MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, and pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and in situ hybridization of glans tissue from the human and rat penis revealed MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicated MC4R in the modulation of penile erectile function and provided evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. The results supported the existence of MC4R-controlled neuronal pathways that control sexual function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12172010" 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="#52" class="mim-tip-reference" title="Xu, B., Goulding, E. H., Zang, K., Cepoi, D., Cone, R. D., Jones, K. R., Tecott, L. H., Reichardt, L. F. <strong>Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.</strong> Nature Neurosci. 6: 736-742, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12796784[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/nn1073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796784">Xu et al. (2003)</a> found that, like MC4R mutants, mouse mutants that express decreased amounts of the brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>) receptor TrkB (<a href="/entry/600456">600456</a>) showed hyperphagia and maturity-onset obesity, suggesting a role for BDNF in energy balance. The authors found that BDNF is an anorexigenic factor that is highly expressed in murine ventromedial hypothalamic (VMH) nuclei and is regulated by feeding status. Deficiency in MC4R signaling reduced expression of BDNF in the VMH, indicating that BDNF and its receptor TrkB are downstream components in the MC4R-mediated control of energy balance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12796784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Balthasar, N., Dalgaard, L. T., Lee, C. E., Yu, J., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R. A., Kenny, C. D., Christiansen, L. M., Edelstein, E., Choi, B., Boss, O., Aschkenasi, C., Zhang, C., Mountjoy, K., Kishi, T., Elmquist, J. K., Lowell, B. B. <strong>Divergence of melanocortin pathways in the control of food intake and energy expenditure.</strong> Cell 123: 493-505, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269339</a>] [<a href="https://doi.org/10.1016/j.cell.2005.08.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269339">Balthasar et al. (2005)</a> devised a strategy to target Mc4r reactivation in specific neurons in Mc4r-null mice. They found that restoration of Mc4r expression in the paraventricular hypothalamus and in a subpopulation of amygdala neurons prevented 60% of the obesity observed in Mc4r-null animals. Rescued animals reduced their food intake toward normal. However, measures of oxygen consumption suggested that their remaining obesity was due to low energy expenditure. <a href="#1" class="mim-tip-reference" title="Balthasar, N., Dalgaard, L. T., Lee, C. E., Yu, J., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R. A., Kenny, C. D., Christiansen, L. M., Edelstein, E., Choi, B., Boss, O., Aschkenasi, C., Zhang, C., Mountjoy, K., Kishi, T., Elmquist, J. K., Lowell, B. B. <strong>Divergence of melanocortin pathways in the control of food intake and energy expenditure.</strong> Cell 123: 493-505, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269339</a>] [<a href="https://doi.org/10.1016/j.cell.2005.08.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269339">Balthasar et al. (2005)</a> concluded that different melanocortin pathways control food intake and energy expenditure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269339" 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">rs2143966223 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2143966223;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=rs2143966223" 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=rs2143966223" 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=RCV000015393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015393</a>
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<p><a href="#48" class="mim-tip-reference" title="Vaisse, C., Clement, K., Guy-Grand, B., Froguel, P. <strong>A frameshift mutation in human MC4R is associated with a dominant form of obesity.</strong> Nature Genet 20: 113-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771699</a>] [<a href="https://doi.org/10.1038/2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771699">Vaisse et al. (1998)</a> used PCR-SSCP with 5 primer pairs covering the entire single exon of MC4R to screen for mutations in 43 individuals with morbid obesity (BMIQ20; <a href="/entry/618406">618406</a>). A single patient was found to have heterozygosity for a frameshift mutation, a 4-bp insertion at nucleotide 732 resulting in expression of a nonfunctional, truncated receptor lacking the sixth and seventh transmembrane domains. The patient was a 35-year-old woman with obesity that developed in infancy. Her birth weight was normal. Her weight was 45 kg with a height of 141 cm at age 10 years, and 80 kg with a height of 163 cm at age 20. Blood glucose and plasmid lipid levels were normal; serum leptin levels were consistent with her adiposity. She belonged to a large family of obese subjects: her mother, sister, niece, and a younger brother were also obese. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771699" 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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MC4R, TYR35TER AND ASP37VAL
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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> rs13447324 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs13447324;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/rs13447324?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=rs13447324" 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=rs13447324" 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"><span class="text-primary">●</span> rs13447325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs13447325;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/rs13447325?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=rs13447325" 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=rs13447325" 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=RCV000015394 OR RCV000015395 OR RCV000202583 OR RCV000255005 OR RCV000435394 OR RCV001174507 OR RCV001262822 OR RCV001699179 OR RCV002504792 OR RCV004017247 OR RCV004797761" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015394, RCV000015395, RCV000202583, RCV000255005, RCV000435394, RCV001174507, RCV001262822, RCV001699179, RCV002504792, RCV004017247, RCV004797761" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015394...</a>
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<p>In 2 obese (BMIQ20; <a href="/entry/618406">618406</a>) probands (BMI, 31.29 kg/m2 and 45.91 kg/m2, respectively), <a href="#24" class="mim-tip-reference" title="Hinney, A., Schmidt, A., Nottebom, K., Heibult, O., Becker, I., Ziegler, A., Gerber, G., Sina, M., Gorg, T., Mayer, H., Siegfried, W., Fichter, M., Remschmidt, H., Hebebrand, J. <strong>Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.</strong> J. Clin. Endocr. Metab. 84: 1483-1486, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199800</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199800">Hinney et al. (1999)</a> identified a C-to-A transversion at nucleotide 105 of the MC4R gene, resulting in a tyr35-to-ter substitution. This mutation led to a truncated protein that encompassed the N-terminal extracellular domain. Both carriers also showed an A-to-T transversion at nucleotide 110, resulting in an asp37-to-val substitution. In both cases these mutations were maternally transmitted, indicating they form a haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913557 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913557;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/rs121913557?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=rs121913557" 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=rs121913557" 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=RCV000015396 OR RCV004760334" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015396, RCV004760334" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015396...</a>
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<p>In a child with severe obesity (BMIQ20; <a href="/entry/618406">618406</a>) child, <a href="#10" class="mim-tip-reference" title="Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J.-P., Guy-Grand, B., Tounian, P. <strong>Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.</strong> J. Pediat. 139: 204-209, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487744</a>] [<a href="https://doi.org/10.1067/mpd.2001.116284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487744">Dubern et al. (2001)</a> identified a G-to-A transition at nucleotide 148 of the MC4R gene, resulting in a valine-to-methionine substitution at codon 50 in the first transmembrane domain of the melanocortin-4 receptor. This mutation was found in heterozygosity in this patient and was not identified in any of the 283 nonobese adults. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487744" 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 time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; <a href="/entry/107941">107941</a>) recruitment, <a href="#32" class="mim-tip-reference" title="Lotta, L. A., Mokrosinski, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., Farooqu, I. S. <strong>Human gain-of-function MC4R variants show signaling bias and protect against obesity.</strong> Cell 177: 597-607, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31002796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31002796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31002796[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2019.03.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31002796">Lotta et al. (2019)</a> observed loss-of-function effects with the V50M mutant in the beta-arrestin-mediated signaling assay, whereas the mutant showed similar effects to wildtype MC4R in the cAMP assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31002796" 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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MC4R, SER58CYS
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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> rs121913558 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913558;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/rs121913558?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=rs121913558" 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=rs121913558" 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=RCV000015397" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015397" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015397</a>
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<p>In 1 of 63 obese (BMIQ20; <a href="/entry/618406">618406</a>) children screened for mutations of MC4R, <a href="#10" class="mim-tip-reference" title="Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J.-P., Guy-Grand, B., Tounian, P. <strong>Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.</strong> J. Pediat. 139: 204-209, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487744</a>] [<a href="https://doi.org/10.1067/mpd.2001.116284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487744">Dubern et al. (2001)</a> identified heterozygosity for an A-to-T transversion at nucleotide 172 of the MC4R gene, resulting in a ser-to-cys substitution at codon 58 in the first transmembrane domain of the melanocortin-4 receptor. This mutation was not identified in any of 283 nonobese adults. The proband's sister, who was also heterozygous for the mutation, had a BMI within the normal range for her age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913559 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913559;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/rs121913559?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=rs121913559" 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=rs121913559" 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=RCV000015398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015398</a>
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<p>In 1 of 63 obese (BMIQ20; <a href="/entry/618406">618406</a>) children, <a href="#10" class="mim-tip-reference" title="Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J.-P., Guy-Grand, B., Tounian, P. <strong>Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.</strong> J. Pediat. 139: 204-209, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487744</a>] [<a href="https://doi.org/10.1067/mpd.2001.116284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487744">Dubern et al. (2001)</a> identified heterozygosity for a T-to-G transversion at nucleotide 305 of the MC4R gene, resulting in an isoleucine-to-serine substitution at codon 102 in the second transmembrane domain of the melanocortin-4 receptor. The proband's mother, who was also heterozygous for the mutation, was of normal weight and had no history of obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487744" 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>Through detailed functional characterization of cell surface expression, ligand binding, and signaling properties, <a href="#47" class="mim-tip-reference" title="Tao, Y.-X., Segaloff, D. L. <strong>Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects.</strong> J. Clin. Endocr. Metab. 90: 5632-5638, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16030156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16030156</a>] [<a href="https://doi.org/10.1210/jc.2005-0519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16030156">Tao and Segaloff (2005)</a> determined that the I102T variant results in loss of function of the MC4R protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16030156" 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 OBESITY (BMIQ20)</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> rs121913560 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913560;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/rs121913560?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=rs121913560" 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=rs121913560" 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=RCV000015399 OR RCV003407337 OR RCV003546455" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015399, RCV003407337, RCV003546455" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015399...</a>
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<p>In 1 of 63 obese (BMIQ20; <a href="/entry/618406">618406</a>) children, <a href="#10" class="mim-tip-reference" title="Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J.-P., Guy-Grand, B., Tounian, P. <strong>Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.</strong> J. Pediat. 139: 204-209, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487744</a>] [<a href="https://doi.org/10.1067/mpd.2001.116284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487744">Dubern et al. (2001)</a> identified an A-to-G transition at nucleotide 508 of the MC4R gene, resulting in an isoleucine-to-valine substitution at codon 170 in the fourth transmembrane domain of the melanocortin-4 receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487744" 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="0009" class="mim-anchor"></a>
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<strong>.0009 OBESITY (BMIQ20)</strong>
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MC4R, ASN274SER
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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> rs121913561 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913561;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/rs121913561?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=rs121913561" 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=rs121913561" 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=RCV000015400 OR RCV001125885 OR RCV001531447 OR RCV003892108" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015400, RCV001125885, RCV001531447, RCV003892108" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015400...</a>
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<p><a href="#38" class="mim-tip-reference" title="Mergen, M., Mergen, H., Ozata, M., Oner, R., Oner, C. <strong>A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity.</strong> J. Clin. Endocr. Metab. 86: 3448-3451, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11443223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11443223</a>] [<a href="https://doi.org/10.1210/jcem.86.7.7809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11443223">Mergen et al. (2001)</a> determined the nucleotide sequence of the entire coding region of the MC4R gene in 40 morbidly obese (BMIQ20; <a href="/entry/618406">618406</a>) subjects from independent families. The authors reported a novel heterozygous mutation, asn274 to ser (N274S), in an obese female (age, 52 years; height, 158 cm; weight, 104 kg; BMI, 41.7 kg/m2). The sister of the proband (age, 55 years; height, 160 cm; weight, 110 kg; BMI, 43 kg/m2) carried the same mutation. Although both sisters were morbidly obese and hypertensive, the proband had normal plasma insulin and fasting blood glucose levels, whereas her sister had type II diabetes mellitus (<a href="/entry/125853">125853</a>). No abnormalities of the reproductive function were present. Despite marked hyperphagia in childhood, both sisters had a history of relatively diminished intensity of appetite after the age of 20. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11443223" 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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<h4>
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<strong>.0010 OBESITY (BMIQ20)</strong>
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MC4R, 1-BP INS, 112A
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015401</a>
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<span class="mim-text-font">
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<p>In a proband and his mother and sister, all with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> identified heterozygosity for a frameshift mutation in the MC4R gene, 112insA, which resulted in complete loss of activity of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="0011" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0011 OBESITY (BMIQ20)</strong>
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MC4R, 4-BP DEL, 211CTCT
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015392 OR RCV003407336" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015392, RCV003407336" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015392...</a>
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</span>
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<span class="mim-text-font">
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<p>In a father and son with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> identified heterozygosity for a frameshift mutation in the MC4R gene, 211delCTCT, which resulted in complete loss of activity of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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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<span class="mim-font">
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<strong>.0012 OBESITY (BMIQ20)</strong>
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MC4R, 2-BP INS, 279GT
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015403</a>
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<p>In each of 2 presumably unrelated families, <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found that the father and 1 child with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>) were heterozygous for a frameshift mutation in the MC4R gene, 279insGT, which resulted in complete loss of activity of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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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<h4>
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<span class="mim-font">
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<strong>.0013 OBESITY (BMIQ20)</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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MC4R, ILE125LYS
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015404 OR RCV004748522" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015404, RCV004748522" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015404...</a>
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</span>
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<span class="mim-text-font">
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<p>In each of 2 presumably unrelated families, <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found that a parent and 1 child with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>) were heterozygous for an ile125-to-lys (I125K) mutation in the MC4R gene. The protein showed no activity on in vitro assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="#54" class="mim-tip-reference" title="Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., O'Rahilly, S. <strong>Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.</strong> Hum. Molec. Genet. 12: 561-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588803</a>] [<a href="https://doi.org/10.1093/hmg/ddg057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588803">Yeo et al. (2003)</a> demonstrated that the I125K mutation was completely unable to generate cAMP in response to ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913562 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913562;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/rs121913562?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=rs121913562" 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=rs121913562" 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=RCV000015405 OR RCV000768578 OR RCV004017248 OR RCV004748523" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015405, RCV000768578, RCV004017248, RCV004748523" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015405...</a>
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<p>In a family with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>) in 8 individuals in 3 successive generations, <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found that affected individuals were heterozygous for a cys271-to-tyr (C271Y) mutation in the MC4R gene. The protein showed no activity on in vitro assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="#54" class="mim-tip-reference" title="Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., O'Rahilly, S. <strong>Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.</strong> Hum. Molec. Genet. 12: 561-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588803</a>] [<a href="https://doi.org/10.1093/hmg/ddg057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588803">Yeo et al. (2003)</a> observed that the C271Y mutation was completely unable to generate cAMP in response to ligand and showed impaired cell surface expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913563 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913563;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/rs121913563?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=rs121913563" 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=rs121913563" 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=RCV000015406 OR RCV000768579 OR RCV002247343 OR RCV002513063 OR RCV003415708" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015406, RCV000768579, RCV002247343, RCV002513063, RCV003415708" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015406...</a>
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<p>In a mother and son with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found heterozygosity for an ala175-to-thr (A175T) mutation in the MC4R gene. The protein showed partial activity on in vitro assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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 time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; <a href="/entry/107941">107941</a>) recruitment, <a href="#32" class="mim-tip-reference" title="Lotta, L. A., Mokrosinski, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., Farooqu, I. S. <strong>Human gain-of-function MC4R variants show signaling bias and protect against obesity.</strong> Cell 177: 597-607, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31002796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31002796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31002796[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2019.03.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31002796">Lotta et al. (2019)</a> observed loss-of-function effects with the A175T mutant compared to wildtype MC4R. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31002796" 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 OBESITY (BMIQ20)</strong>
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MC4R, ILE316SER
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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> rs121913564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913564;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/rs121913564?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=rs121913564" 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=rs121913564" 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=RCV000015407 OR RCV000778539 OR RCV004017249" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015407, RCV000778539, RCV004017249" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015407...</a>
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<p>In a family in which there was extensive consanguinity, <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found that early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>) in 6 individuals in 2 generations was associated with heterozygosity for an ile316-to-ser (I316S) mutation in the MC4R gene. In a second, unrelated family, the authors found that early-onset obesity in a mother and 3 daughters was associated with this mutation. The protein showed partial activity on in vitro assay in both families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="#54" class="mim-tip-reference" title="Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., O'Rahilly, S. <strong>Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.</strong> Hum. Molec. Genet. 12: 561-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588803</a>] [<a href="https://doi.org/10.1093/hmg/ddg057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588803">Yeo et al. (2003)</a> observed that the I316S mutant protein showed reduced affinity for alpha-MSH (see <a href="/entry/176830">176830</a>), but retained normal affinity for the antagonist agouti-related protein (AGRP; <a href="/entry/602311">602311</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588803" 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 time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; <a href="/entry/107941">107941</a>) recruitment, <a href="#32" class="mim-tip-reference" title="Lotta, L. A., Mokrosinski, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., Farooqu, I. S. <strong>Human gain-of-function MC4R variants show signaling bias and protect against obesity.</strong> Cell 177: 597-607, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31002796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31002796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31002796[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2019.03.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31002796">Lotta et al. (2019)</a> observed loss-of-function effects with the I316S mutant compared to wildtype MC4R. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31002796" 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 OBESITY (BMIQ20)</strong>
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MC4R, TYR287TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917829 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917829;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=rs121917829" 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=rs121917829" 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=RCV000015408 OR RCV004017250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015408, RCV004017250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015408...</a>
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<p>In a proband with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found homozygosity for a tyr287-to-ter (Y287X) mutation in the MC4R gene; the mother and a sister were also obese but were heterozygous for the mutation. On in vitro assay, the protein showed no activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="#54" class="mim-tip-reference" title="Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., O'Rahilly, S. <strong>Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.</strong> Hum. Molec. Genet. 12: 561-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588803</a>] [<a href="https://doi.org/10.1093/hmg/ddg057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588803">Yeo et al. (2003)</a> demonstrated that the Y287X mutation showed impaired cell surface expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588803" 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">rs121913565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913565;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=rs121913565" 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=rs121913565" 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=RCV000015409" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015409" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015409</a>
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<p>In a proband with early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found homozygosity for an asn97-to-asp (N97D) mutation in the MC4R gene; her consanguineous parents and a sister were also obese but were heterozygous for the mutation. On in vitro assay, the protein showed no activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="#54" class="mim-tip-reference" title="Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., O'Rahilly, S. <strong>Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.</strong> Hum. Molec. Genet. 12: 561-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588803</a>] [<a href="https://doi.org/10.1093/hmg/ddg057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588803">Yeo et al. (2003)</a> demonstrated that the N97D mutation was completely unable to generate cAMP in response to ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588803" 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="0019" class="mim-anchor"></a>
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<strong>.0019 OBESITY (BMIQ20)</strong>
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MC4R, ASN62SER
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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> rs121913566 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913566;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/rs121913566?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=rs121913566" 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=rs121913566" 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=RCV000015410 OR RCV004017251" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015410, RCV004017251" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015410...</a>
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<p>In an inbred family in which 10 individuals in 3 generations had early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#11" class="mim-tip-reference" title="Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., O'Rahilly, S. <strong>Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.</strong> New Eng. J. Med. 348: 1085-1095, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646665</a>] [<a href="https://doi.org/10.1056/NEJMoa022050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646665">Farooqi et al. (2003)</a> found that the proband and 4 of his cousins were homozygous for an asn62-to-ser (N62S) mutation in the MC4R gene. The consanguineous parents in each case were heterozygous for the mutation and showed obesity that was less severe. On in vitro assay, the protein showed partial activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646665" 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="0020" class="mim-anchor"></a>
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<strong>.0020 OBESITY (BMIQ20)</strong>
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MC4R, 15-BP DEL
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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> rs777077280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777077280;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/rs777077280?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=rs777077280" 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=rs777077280" 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=RCV000015411" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015411" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015411</a>
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<p>In a female patient with onset of obesity (BMIQ20; <a href="/entry/618406">618406</a>) at less than 5 years of age, <a href="#8" class="mim-tip-reference" title="Donohoue, P. A., Tao, Y.-X., Collins, M., Yeo, G. S. H., O'Rahilly, S., Segaloff, D. L. <strong>Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female.</strong> J. Clin. Endocr. Metab. 88: 5841-5845, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14671178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14671178</a>] [<a href="https://doi.org/10.1210/jc.2003-030903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14671178">Donohoue et al. (2003)</a> detected an in-frame deletion in the MC4R gene of codons 88 through 92 (delta88-92). These codons were predicted to lie within the second transmembrane domain. Functional analysis revealed that the mutant receptor was expressed well on the cell surface but was completely devoid of ligand binding and cAMP generation in response to agonist stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671178" 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 OBESITY (BMIQ20)</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> rs13447331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs13447331;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/rs13447331?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=rs13447331" 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=rs13447331" 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=RCV000015412 OR RCV000414065 OR RCV000768580 OR RCV004017252 OR RCV004748524" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015412, RCV000414065, RCV000768580, RCV004017252, RCV004748524" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015412...</a>
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<p>In a 14.8-year-old boy with severe early-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>), <a href="#49" class="mim-tip-reference" title="Valli-Jaakola, K., Lipsanen-Nyman, M., Oksanen, L., Hollenberg, A. N., Kontula, K., Bjorbaek, C., Schalin-Jantti, C. <strong>Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults.</strong> J. Clin. Endocr. Metab. 89: 940-945, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764818</a>] [<a href="https://doi.org/10.1210/jc.2003-031182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764818">Valli-Jaakola et al. (2004)</a> identified a ser127-to-leu (S127L) mutation in the melanocortin-4 receptor. Abnormal weight gain began in the second year of life. The patient presented with acanthosis nigricans in the neck and axillae and demonstrated marked hyperinsulinemia during an oral glucose tolerance test despite normal glucose tolerance. Blood pressure was normal for age. His father, in whom the same mutation was found, suffered form severe obesity in childhood although the phenotype became less apparent in adulthood. Functional studies in transiently transfected 239T cells indicated that signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma-1-MSH (see <a href="/entry/176830">176830</a>) were impaired. <a href="#49" class="mim-tip-reference" title="Valli-Jaakola, K., Lipsanen-Nyman, M., Oksanen, L., Hollenberg, A. N., Kontula, K., Bjorbaek, C., Schalin-Jantti, C. <strong>Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults.</strong> J. Clin. Endocr. Metab. 89: 940-945, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764818</a>] [<a href="https://doi.org/10.1210/jc.2003-031182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764818">Valli-Jaakola et al. (2004)</a> noted that this mutation had been reported by <a href="#34" class="mim-tip-reference" title="Lubrano-Berthelier, C., Durand, E., Dubern, B., Shapiro, A., Dazin, P., Weill, J., Ferron, C., Froguel, P., Vaisse, C. <strong>Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations.</strong> Hum. Molec. Genet. 12: 145-153, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499395</a>] [<a href="https://doi.org/10.1093/hmg/ddg016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499395">Lubrano-Berthelier et al. (2003)</a> and <a href="#23" class="mim-tip-reference" title="Hinney, A., Hohmann, S., Geller, F., Vogel, C., Hess, C., Wermter, A.-K., Brokamp, B., Goldschmidt, H., Siegfried, W., Remschmidt, H., Schafer, H., Gudermann, T., Hebebrand, J. <strong>Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity.</strong> J. Clin. Endocr. Metab. 88: 4258-4267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970296</a>] [<a href="https://doi.org/10.1210/jc.2003-030233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970296">Hinney et al. (2003)</a> in a total of 4 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12970296+14764818+12499395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs13447339 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs13447339;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/rs13447339?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=rs13447339" 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=rs13447339" 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=RCV000015413 OR RCV000500812 OR RCV001249014 OR RCV002510907 OR RCV003935293" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015413, RCV000500812, RCV001249014, RCV002510907, RCV003935293" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015413...</a>
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<p>In an obese (BMIQ20; <a href="/entry/618406">618406</a>) child of first-cousin parents of North African origin, <a href="#35" class="mim-tip-reference" title="Lubrano-Berthelier, C., Le Stunff, C., Bougneres, P., Vaisse, C. <strong>A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans.</strong> J. Clin. Endocr. Metab. 89: 2028-2032, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15126516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15126516</a>] [<a href="https://doi.org/10.1210/jc.2003-031993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15126516">Lubrano-Berthelier et al. (2004)</a> detected a homozygous 2-bp deletion in the MC4R gene (delta750-751GA). MC4R activity was completely absent. The parents and all sibs of the proband were heterozygous for the mutation. <a href="#35" class="mim-tip-reference" title="Lubrano-Berthelier, C., Le Stunff, C., Bougneres, P., Vaisse, C. <strong>A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans.</strong> J. Clin. Endocr. Metab. 89: 2028-2032, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15126516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15126516</a>] [<a href="https://doi.org/10.1210/jc.2003-031993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15126516">Lubrano-Berthelier et al. (2004)</a> compared the clinical and endocrine characteristics of this patient with those observed in leptin receptor (<a href="/entry/601007">601007</a>)-deficient patients. They concluded that in humans, the MC4R mediates most of the anorectic effects of leptin (<a href="/entry/164160">164160</a>) in early childhood. In contrast, MC4R does not mediate the effect of leptin on linear growth and other endocrine axes. In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15126516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015414 OR RCV004748525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015414, RCV004748525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015414...</a>
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<p>In a study of the MC4R gene in 750 Danish men with juvenile-onset obesity (BMIQ20; <a href="/entry/618406">618406</a>) and 706 control subjects, <a href="#28" class="mim-tip-reference" title="Larsen, L. H., Echwald, S. M., Sorensen, T. I. A., Andersen, T., Wulff, B. S., Pedersen, O. <strong>Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity.</strong> J. Clin. Endocr. Metab. 90: 219-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15486053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15486053</a>] [<a href="https://doi.org/10.1210/jc.2004-0497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15486053">Larsen et al. (2005)</a> detected a novel missense mutation in 1 subject, ala219 to val (A219V), that arose from a 656C-T transition. The A219V variant showed significant impairment of cAMP-induced activity in response to melanotan II (MTII) compared with the wildtype receptor (34%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15486053" 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 time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; <a href="/entry/107941">107941</a>) recruitment, <a href="#32" class="mim-tip-reference" title="Lotta, L. A., Mokrosinski, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., Farooqu, I. S. <strong>Human gain-of-function MC4R variants show signaling bias and protect against obesity.</strong> Cell 177: 597-607, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31002796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31002796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31002796[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2019.03.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31002796">Lotta et al. (2019)</a> observed loss-of-function effects with the A219V mutant in the cAMP assay, whereas the mutant showed similar effects to wildtype MC4R in the beta-arrestin-mediated signaling assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31002796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs2229616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2229616;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/rs2229616?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=rs2229616" 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=rs2229616" 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=RCV000202600 OR RCV000445452 OR RCV000768671 OR RCV000768672 OR RCV001699064 OR RCV001778791 OR RCV002057039 OR RCV003977552" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202600, RCV000445452, RCV000768671, RCV000768672, RCV001699064, RCV001778791, RCV002057039, RCV003977552" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202600...</a>
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<p><a href="#15" class="mim-tip-reference" title="Gotoda, T., Scott, J., Aitman, T. J. <strong>Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin.</strong> Diabetologia 40: 976-979, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9267995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9267995</a>] [<a href="https://doi.org/10.1007/s001250050777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9267995">Gotoda et al. (1997)</a> sequenced the MC4R gene in 40 morbidly obese white British men with body mass indexes (BMIs) greater than 35, and 10 lean men with BMIs less than 18, and identified heterozygosity for a 307G-A transition, resulting in a val103-to-ile (V103I) substitution in 2 obese men. No other nucleotide alterations were found. The prevalence of the V103I missense variant was then studied in 322 white British men from a population-based epidemiologic survey, including 190 men with BMI greater than 28 and 132 men with BMI less than 22. No homozygotes for V103I were identified, and the frequency of heterozygosity for the V103I substitution was similar between the 2 groups (4.2% and 4.5%). In addition, there was no significant difference in BMI, total skinfold thickness, or plasma insulin and glucose levels between heterozygotes and V103 homozygotes. The authors concluded that coding sequence mutations in MC4R were unlikely to be a major cause of human obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9267995" 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 SSCP analysis, <a href="#16" class="mim-tip-reference" title="Gu, W., Tu, Z., Kleyn, P. W., Kissebah, A., Duprat, L., Lee, J., Chin, W., Maruti, S., Deng, N., Fisher, S. L., Franco, L. S., Burn, P., Yagaloff, K. A., Nathan, J., Heymsfield, S., Albu, J., Pi-Sunyer, F. X., Allison, D. B. <strong>Identification and functional analysis of novel human melanocortin-4 receptor variants.</strong> Diabetes 48: 635-639, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078568</a>] [<a href="https://doi.org/10.2337/diabetes.48.3.635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10078568">Gu et al. (1999)</a> screened the entire MC4R coding region in 190 individuals of various body sizes and identified heterozygosity for the V103I allele in 7 subjects, including 4 (3.6%) of 110 who were extremely obese (BMI greater than 50), 1 (3.3%) of 30 who were obese (BMI between 30 and 50), none of 3 who were intermediate (BMI greater than 25), and 2 (4.3%) of 47 who were lean (BMI less than 25). Functional analysis of the V103I variant in both stably and transiently transfected 293 cells showed dose-response patterns upon activation by melanocortin peptides that were not significantly different from those of wildtype MC4R. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10078568" 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="Hinney, A., Schmidt, A., Nottebom, K., Heibult, O., Becker, I., Ziegler, A., Gerber, G., Sina, M., Gorg, T., Mayer, H., Siegfried, W., Fichter, M., Remschmidt, H., Hebebrand, J. <strong>Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.</strong> J. Clin. Endocr. Metab. 84: 1483-1486, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199800</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199800">Hinney et al. (1999)</a> screened the coding region of the MC4R gene in 306 extremely obese children and adolescents (mean BMI, approximately 34.4), 25 healthy underweight students (mean BMI, approximately 17), 52 normal-weight students (mean BMI, 22), 51 inpatients with anorexia nervosa (mean BMI, approximately 14), and 27 patients with bulimia nervosa (mean BMI, approximately 22). The V103I variant was detected at similar frequencies in all groups, confirming the findings of <a href="#15" class="mim-tip-reference" title="Gotoda, T., Scott, J., Aitman, T. J. <strong>Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin.</strong> Diabetologia 40: 976-979, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9267995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9267995</a>] [<a href="https://doi.org/10.1007/s001250050777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9267995">Gotoda et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9267995+10199800" 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>Obesity, Resistance to</em></strong></p><p>
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In a transmission/disequilibrium test on 520 trios with obesity, <a href="#13" class="mim-tip-reference" title="Geller, F., Reichwald, K., Dempfle, A., Illig, T., Vollmert, C., Herpertz, S., Siffert, W., Platzer, M., Hess, C., Gudermann, T., Biebermann, H., Wichmann, H.-E., Schafer, H., Hinney, A., Hebebrand, J. <strong>Melanocortin-4 receptor gene variant 1103 is negatively associated with obesity.</strong> Am. J. Hum. Genet. 74: 572-581, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14973783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14973783</a>] [<a href="https://doi.org/10.1086/382490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14973783">Geller et al. (2004)</a> unexpectedly observed a lower transmission rate of the 103I allele (p = 0.017) (see <a href="/entry/618406">618406</a>). Metaanalysis of combined data from 7,713 individuals, primarily samples of European origin, in 2 large case-control studies and 12 published studies demonstrated a negative association of the 103I allele with obesity (odds ratio, 0.69; p = 0.03). Additional screening of 4 other ethnic groups (Tanzanians, African Americans, Chinese, and Japanese) showed 103I frequencies ranging from 0 to 6.5%. Functional analysis in COS-7 cells transiently transfected with the V103I mutant or wildtype MC4R revealed similar cAMP levels at baseline, with no consistent differences in maximum or EC50 values after stimulation with 3 agonists, and the binding properties of the mutant and wildtype proteins were also indistinguishable. Noting the apparent protective effect against obesity, the authors suggested that variation in the MC4R gene might entail both loss and gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14973783" 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="Heid, I. M., Vollmert, C., Hinney, A., Doring, A., Geller, F., Lowel, H., Wichmann, H.-E., Illig, T., Hebebrand, J., Kronenberg, F., the KORA group. <strong>Association of the 1031 MC4R allele with decreased body mass in 7937 participants of two population based surveys.</strong> J. Med. Genet. 42: e21, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805150</a>] [<a href="https://doi.org/10.1136/jmg.2004.027011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805150">Heid et al. (2005)</a> analyzed data from 2 large German population-based surveys with a total of 7,937 participants. By linear regression, they found a significant decrease of 0.52 BMI units (p = 0.043) for heterozygous carriers of the V103I variant, which was observed in 3.7% of participants. Logistic regression analysis yielded a significantly negative association of the MC4R variant with above-average weight (odds ratio, 0.75; p = 0.017). Similar results were obtained in a comparison of obese (BMI greater than 30) to nonobese participants of either sex (odds ratio, 0.69; p = 0.026). The authors concluded that the V103I polymorphism could be regarded as contributing to polygenetically regulated body weight. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805150" 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 study of 452,300 participants of European ancestry from the UK Biobank database, <a href="#32" class="mim-tip-reference" title="Lotta, L. A., Mokrosinski, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., Farooqu, I. S. <strong>Human gain-of-function MC4R variants show signaling bias and protect against obesity.</strong> Cell 177: 597-607, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31002796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31002796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31002796[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2019.03.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31002796">Lotta et al. (2019)</a> found that the V103I variant was the most common nonsynonymous variant (allele frequency, 2%). Time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; <a href="/entry/107941">107941</a>) recruitment showed gain-of-function effects with the V103I variant, which exhibited significant bias towards beta-arrestin-mediated signaling. Previously reported associations of V103I with lower BMI and obesity risk were confirmed in this analysis. In metaanalyses of genetic association studies involving more than 600,000 individuals, V103I was associated with lower risk of type 2 diabetes (p = 7 x 10(-7)) and of coronary artery disease (p = 0.003), as well as with lower diastolic blood pressure and resting heart rate. Functional analysis showed that the magnitude and duration of ligand-induced ERK1/2 phosphorylation was also increased (p = 0.009). Confocal microscopy of transfected COS-7 cells demonstrated that whereas wildtype MC4R translocated from the membrane into the cytoplasm upon agonist stimulation, the V103I mutant remained at the cell surface. Fluorescence-activated cell-sorting assay of transfected HeLa cells showed a 23% reduction in cell surface expression of wildtype MC4R upon ligand stimulation, whereas there was no change in V103I expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31002796" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30068297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30068297</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30068297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690102</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12690102" 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.M211326200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2003-031175" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.aaz8995" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 08/28/2020
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Ada Hamosh - updated : 06/26/2020<br>Marla J. F. O'Neill - updated : 05/01/2019<br>Bao Lige - updated : 08/06/2018<br>Ada Hamosh - updated : 05/15/2017<br>Ada Hamosh - updated : 06/23/2015<br>Patricia A. Hartz - updated : 2/7/2014<br>Ada Hamosh - updated : 8/29/2012<br>Ada Hamosh - updated : 8/8/2011<br>George E. Tiller - updated : 1/5/2011<br>Ada Hamosh - updated : 1/15/2010<br>Marla J. F. O'Neill - updated : 7/16/2008<br>John A. Phillips, III - updated : 3/31/2008<br>John A. Phillips, III - updated : 7/16/2007<br>John A. Phillips, III - updated : 7/16/2007<br>John A. Phillips, III - updated : 5/14/2007<br>John A. Phillips, III - updated : 4/4/2006<br>John A. Phillips, III - updated : 7/26/2005<br>John A. Phillips, III - updated : 7/6/2005<br>John A. Phillips, III - updated : 4/29/2005<br>John A. Phillips, III - updated : 4/19/2005<br>George E. Tiller - updated : 4/19/2005<br>John A. Phillips, III - updated : 4/11/2005<br>John Logan Black, III - updated : 3/2/2005<br>George E. Tiller - updated : 10/26/2004<br>Cassandra L. Kniffin - updated : 6/24/2003<br>Cassandra L. Kniffin - updated : 6/16/2003<br>Victor A. McKusick - updated : 4/17/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Victor A. McKusick - updated : 3/20/2003<br>Victor A. McKusick - updated : 10/9/2002<br>George E. Tiller - updated : 9/23/2002<br>Ada Hamosh - updated : 8/7/2002<br>John A. Phillips, III - updated : 3/13/2002<br>Ada Hamosh - updated : 9/24/2001<br>Victor A. McKusick - updated : 11/27/2000<br>Victor A. McKusick - updated : 8/30/2000<br>Victor A. McKusick - updated : 3/15/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Victor A. McKusick - updated : 12/6/1999<br>Victor A. McKusick - updated : 12/23/1998<br>Carol A. Bocchini - updated : 11/17/1998<br>Victor A. McKusick - updated : 9/23/1998<br>Victor A. McKusick - updated : 2/7/1997
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Creation Date:
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Victor A. McKusick : 10/1/1993
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carol : 01/07/2025
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carol : 08/28/2020<br>alopez : 06/26/2020<br>carol : 07/09/2019<br>carol : 05/07/2019<br>carol : 05/02/2019<br>carol : 05/01/2019<br>mgross : 08/06/2018<br>carol : 08/21/2017<br>alopez : 08/17/2017<br>alopez : 05/15/2017<br>alopez : 06/23/2015<br>mgross : 2/7/2014<br>mcolton : 2/7/2014<br>alopez : 9/4/2012<br>alopez : 9/4/2012<br>terry : 8/29/2012<br>alopez : 8/8/2011<br>wwang : 1/19/2011<br>terry : 1/5/2011<br>alopez : 1/19/2010<br>alopez : 1/19/2010<br>terry : 1/15/2010<br>alopez : 6/3/2009<br>alopez : 7/16/2008<br>carol : 3/31/2008<br>alopez : 7/16/2007<br>alopez : 7/16/2007<br>alopez : 5/14/2007<br>wwang : 8/1/2006<br>alopez : 4/4/2006<br>alopez : 8/9/2005<br>alopez : 7/26/2005<br>alopez : 7/6/2005<br>alopez : 4/29/2005<br>alopez : 4/19/2005<br>alopez : 4/19/2005<br>alopez : 4/11/2005<br>mgross : 4/5/2005<br>tkritzer : 3/2/2005<br>tkritzer : 11/2/2004<br>terry : 10/26/2004<br>alopez : 7/28/2003<br>carol : 7/9/2003<br>carol : 7/7/2003<br>ckniffin : 6/24/2003<br>carol : 6/17/2003<br>ckniffin : 6/16/2003<br>carol : 5/8/2003<br>tkritzer : 5/5/2003<br>tkritzer : 4/25/2003<br>tkritzer : 4/25/2003<br>terry : 4/17/2003<br>carol : 4/16/2003<br>terry : 4/8/2003<br>tkritzer : 3/20/2003<br>tkritzer : 3/20/2003<br>tkritzer : 3/20/2003<br>carol : 1/24/2003<br>tkritzer : 10/17/2002<br>tkritzer : 10/9/2002<br>tkritzer : 10/9/2002<br>cwells : 9/23/2002<br>alopez : 8/8/2002<br>terry : 8/7/2002<br>alopez : 3/13/2002<br>alopez : 3/13/2002<br>alopez : 9/25/2001<br>terry : 9/24/2001<br>mcapotos : 12/11/2000<br>mcapotos : 12/6/2000<br>terry : 11/27/2000<br>alopez : 8/30/2000<br>mcapotos : 4/6/2000<br>mcapotos : 4/5/2000<br>terry : 3/15/2000<br>mgross : 1/11/2000<br>terry : 12/20/1999<br>terry : 12/20/1999<br>mgross : 12/9/1999<br>terry : 12/6/1999<br>mgross : 9/28/1999<br>alopez : 12/23/1998<br>alopez : 12/23/1998<br>terry : 12/23/1998<br>terry : 11/17/1998<br>carol : 11/16/1998<br>joanna : 9/28/1998<br>joanna : 9/28/1998<br>alopez : 9/24/1998<br>joanna : 9/23/1998<br>dkim : 7/2/1998<br>alopez : 6/2/1997<br>mark : 2/7/1997<br>terry : 2/4/1997<br>carol : 9/1/1994<br>carol : 10/7/1993<br>carol : 10/1/1993
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<strong>*</strong> 155541
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MELANOCORTIN 4 RECEPTOR; MC4R
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<em>Alternative titles; symbols</em>
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MCR RECEPTOR
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<strong><em>HGNC Approved Gene Symbol: MC4R</em></strong>
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Cytogenetic location: 18q21.32
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:60,371,062-60,372,775 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Inheritance
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Phenotype <br /> mapping key
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18q21.32
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{Obesity, resistance to (BMIQ20)}
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618406
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Autosomal dominant; Autosomal recessive
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3
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Obesity (BMIQ20)
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618406
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Autosomal dominant; Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>Gantz et al. (1993) cloned a fourth member of the melanocortin receptor family of 7-transmembrane G-protein linked receptors. By Northern blot analysis and in situ hybridization, the melanocortin-4 receptor (MC4R) was found to be expressed primarily in the brain; its expression was notably absent in the adrenal cortex, melanocytes, and placenta. The profile of responses of MC4R, transfected into COS-1 cells and L cells, to different melanocortins distinguished it from the previously described melanocortin receptors. (See 155555, 202200, and 155540.) MC4R is a 333-amino acid protein encoded by a single exon (Yeo et al., 1998). </p>
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<strong>Mapping</strong>
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<p>By means of fluorescence chromosomal in situ hybridization, Gantz et al. (1993) localized the MC4R gene to chromosome 18q21.3. By fluorescence in situ hybridization (FISH), Magenis et al. (1994) mapped the MC4R gene to 18q22. Using FISH and radiation hybrid mapping, Sundaramurthy et al. (1998) localized the MC4R gene to 18q22. </p>
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<strong>Gene Function</strong>
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<p>Nonsense-mediated decay (NMD) inhibits the accumulation of nonsense- or frameshift-mutated mRNA and thus minimizes the synthesis of truncated proteins with potential dominant-negative effects. Brocke et al. (2002) investigated the NMD sensitivity of nonsense-mutated transcripts of MC4R. Nonsense-mutated variants of MC4R transcripts were stable and expressed truncated proteins that were detectable in the lysates of transfected cells. The authors hypothesized that the lack of necessity for splicing in the naturally intronless MC4R gene may allow it to escape from NMD. </p><p>By using a combination of pharmacologic, molecular genetic, electrophysiologic, and feeding studies, Mineur et al. (2011) found that activation of hypothalamic alpha-3 (118503)-beta-4 (118509) nicotinic acetylcholine receptors leads to activation of proopiomelanocortin (POMC; 176830) neurons. POMC neurons and subsequent activation of melanocortin-4 receptors were critical for nicotinic-induced decreases in food intake in mice. The study of Mineur et al. (2011) demonstrated that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identified critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite. </p><p>Lim et al. (2012) showed that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor (DRD1; 126449)-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin-4 receptor. Stress-elicited increases in behavioral measurements of anhedonia, but not increases in measurements of behavioral despair, are prevented by blocking these melanocortin-4 receptor-mediated synaptic changes in vivo. Lim et al. (2012) concluded that stress-elicited anhedonia requires a neuropeptide-triggered, cell type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression. </p><p>In mice, Ghamari-Langroudi et al. (2015) showed that regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by alpha-melanocyte-stimulating hormone (alpha-MSH; see 176830) and Agouti-related protein (AGRP; 602311) can be mediated independently of G-alpha-s (see 139320) signaling by ligand-induced coupling of Mc4r to closure of inwardly rectifying potassium channel Kir7.1 (603208). Furthermore, Agrp is a biased agonist that hyperpolarizes neurons by binding to Mc4r and opening Kir7.1, independently of its inhibition of alpha-Msh binding. Consequently, Kir7.1 signaling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of Mc4r to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signaling, including the gene dosage effect of Mc4r and the sustained effects of Agrp on food intake. </p><p>Through molecular and genetic analyses in mice, Mosialou et al. (2017) identified lipocalin-2 (LCN2; 600181) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrated that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived Lcn2 inhibits food intake. Lcn2 crosses the blood-brain barrier, binds to Mc4r in the paraventricular and ventromedial neurons of the hypothalamus, and activates an Mc4r-dependent anorexigenic (appetite-suppressing) pathway. Mosialou et al. (2017) concluded that their results identified Lcn2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and showed that the control of appetite is an endocrine function of bone. </p><p>Siljee et al. (2018) noted that MC4R localizes to the cell membrane when expressed in unciliated heterologous cells. However, they found that human MC4R with a C-terminal GFP tag localized to primary cilia in ciliated cells in vitro. Using a transgenic mouse line, the authors confirmed that Sim1 (603128)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN) were ciliated. Confocal imaging of the PVN of knockin mice expressing MC4R-GFP demonstrated that MC4R colocalized with Adcy3 (600291) at primary cilia of a subset of PVN neurons in vivo. Human MC4R with obesity (618406)-associated mutations in the third intracellular domain had significantly decreased ciliary localization when expressed in mouse IMCD3 cells. In vivo analysis using transgenic mice revealed that one of the MC4R mutant proteins failed to colocalize with Adcy3 at primary cilia, suggesting that localization of MC4R to primary cilia is essential for its function. Inhibition of Adcy3 at primary cilia of Mc4r-expressing neurons of mice increased their food intake and was sufficient to cause obesity compared with controls. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Yu et al. (2020) reported the crystal structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca(2+) was identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca(2+) increased the affinity and potency of the endogenous agonist alpha-melanocyte-stimulating hormone (alpha-MSH; see POMC, 176830) at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1 (KCNJ13; 603208), while lacking cAMP stimulation, highlighted a heterotrimeric GTP-binding protein-independent mechanism for this signaling modality. Yu et al. (2020) concluded that MC4R is a structurally divergent G protein-coupled receptor (GPCR) with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>Yeo et al. (1998) and Vaisse et al. (1998) described a severely obese (BMIQ20; 618406) child and adult, respectively, with heterozygous mutations in the MC4R gene: a 4-bp deletion (155541.0001) in the child and a 4-bp insertion (155541.0002) in the adult. The mutations segregated with obesity in both families in a pattern consistent with autosomal dominant inheritance. Molecular abnormalities have been identified in autosomal recessive severe obesity involving the leptin gene (164160.0001), the leptin receptor gene (601007.0002), the prohormone convertase-1 gene (PC1; 162150.0001), and the proopiomelanocortin gene (POMC; 176830.0001). Hypogonadotropic hypogonadism is found in association with mutations in the leptin, leptin receptor, and PC1 genes, and hypoadrenalism is found with POMC and PC1 gene mutations; short stature is associated with mutations in the leptin receptor gene. There was no evidence of impaired adrenal function in the MC4R-deficient subjects; sexual development and fertility were normal, and affected subjects were tall, which was of interest given the increased linear growth exhibited by heterozygous Mc4r-deficient mice. </p><p>By SSCP, Hinney et al. (1999) screened the coding region of the MC4R gene in 306 extremely obese children and adolescents, 25 healthy underweight students, 52 normal weight individuals, 51 inpatients with anorexia nervosa (606788), and 27 patients with bulimia nervosa (607499). Several mutations were identified, including a 4-bp deletion (155541.0001) that resulted in a frameshift, yielding a truncated protein. This mutation had been assumed to be associated with dominantly inherited morbid obesity in humans. Both the index patient (body mass index (BMI), 42.06 kg/m2; height, 171 cm; age, 19.6 years) and her mother (BMI, 37.55 kg/m2; height, 164 cm; age, 42.5 years) were heterozygous for this deletion. A tyr35-to-ter substitution (155541.0003) was detected in 2 obese probands (BMI, 31.29 kg/m2 and 45.91 kg/m2, respectively); this mutation led to a truncated protein that encompassed the N-terminal extracellular domain. Both carriers also showed an asp37-to-val mutation in cis. In both cases these mutations were transmitted from their obese mothers, indicating they form a haplotype. A male obese proband harbored 2 missense mutations, and 4 different missense mutations were detected in 4 different male probands. All mutations in the MC4R gene were found only in extremely obese individuals whose BMIs were all greater than the 99th percentile. An ile251-to-leu (I251L) polymorphism was found in similar frequencies in all groups studied. The authors concluded that MC4R mutations are not uncommon. While the data supported dominantly inherited obesity because of the 3 obese probands with haploinsufficiency, the functional significance of the missense mutations remained to be determined. </p><p>Sina et al. (1999) extended the MC4R mutation screen to another 186 extremely obese children and adolescents and identified an additional haploinsufficiency carrier, bringing the total number of mutation-carrying obese patients identified to 4. They genotyped and phenotyped 43 family members of these 4 index patients. A total of 19 mutation carriers were identified. Extreme obesity was the predominating phenotype; however, moderate obesity occurred in 3 of the carriers. No other specific phenotypic abnormalities were detected. Female haploinsufficiency carriers were heavier than male carriers in the respective families, a finding similar to findings in Mc4r-knockout mice. </p><p>Dubern et al. (2001) identified heterozygous missense MC4R mutations (155541.0005-155541.0008) in 4 of 63 unrelated children with severe obesity. The same mutation was not found in any of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Dubern et al. (2001) concluded that MC4R mutations may be a nonnegligible cause of severe obesity in children with variable expression and penetrance. </p><p>Jacobson et al. (2002) determined the prevalence of mutations in the coding and flanking regions of the MC4R gene in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family study, and a Memphis cohort. A total of 433 white and 95 black subjects (94% females) were screened for mutations by direct sequencing. Three previously described missense variants and 9 novel (3 missense, 6 silent) variants were detected. None of them showed significant association with obesity or related phenotypes. In addition, 2 novel deletions were found in 2 heterozygous obese women which were predicted to encode a truncated nonfunctional receptor. No pathogenic mutations were found among obese blacks or nonobese controls. Furthermore, none of the null mutations found in other populations was present in this sample. The authors concluded that their results do not support the prevailing notion that sequence variation in the MC4R gene is a frequent cause of human obesity. </p><p>Farooqi et al. (2003) stated that MC4R deficiency is the most common form of monogenic obesity. To define the clinical spectrum, mode of inheritance, genotype-phenotype correlations, and pathophysiologic mechanisms leading to obesity, they determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. In 29 probands (5.8%), they found mutations in MC4R (see, e.g., 155541.0010-155541.0019); 23 were heterozygotes and 6 were homozygotes. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual signaling capacity had a less severe phenotype. Thus, MC4R mutations are inherited in a codominant manner. The correlation between the signaling properties of these mutant receptors and energy intake emphasized the key role of this receptor in the control of eating behavior. </p><p>By means of transient transfection in vitro, Yeo et al. (2003) examined the functional properties of 12 different mutations in human MC4R that result in severe, familial, early-onset obesity. Of the 9 missense mutants studied, 4 (including 155541.0013, 155541.0014, and 155541.0018) were completely unable to generate cAMP in response to ligand and 5 were partially impaired. Four (including 155541.0014 and 155541.0017) showed impaired cell surface expression and 6 showed reduced ligand binding. The mutant protein I316S (155541.0016) showed reduced affinity for alpha-MSH but retained normal affinity for the antagonist agouti-related protein (AGRP; 602311). None of the mutations inhibited signaling through cotransfected wildtype receptors. </p><p>In a cohort of 172 patients presenting with severe childhood obesity and a family history of obesity, Lubrano-Berthelier et al. (2003) screened for mutations in the coding region of the MC4R gene and identified 3 heterozygous MC4R mutations in 3 patients. A functional analysis of 14 MC4R mutations, including the 3 identified in this study, indicated that all mutations altered the activation of the receptor by the endogenous agonist alpha-MSH (see 176830). Lubrano-Berthelier et al. (2003) further demonstrated that greater than 80% of childhood obesity-associated heterozygous MC4R mutations led to intracellular retention of the receptor. </p><p>Branson et al. (2003) sequenced the complete MC4R coding region and the leptin-binding domain of the leptin receptor (LEPR; 601007) in 469 severely obese white subjects (370 women and 99 men). Normal-weight controls were 15 women and 10 men without a history of dieting or a family history of obesity. MC4R mutations, including 5 novel variants, were found in 24 obese subjects (5.1%) and 1 control (4%). Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and BMI with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2% of obese subjects without mutations and none of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha-MSH, the ligand of MC4R. List and Habener (2003) commented on the possible importance of ethnic background in the frequency of mutations in MC4R in obesity. They also suggested that the findings of Branson et al. (2003) be interpreted with caution, as they differed from earlier findings of a binge-eating disorder prevalence of 5% among carriers of MC4R mutations (Sina et al., 1999). </p><p>In detailed pharmacologic studies of 11 different missense mutations in the MC4R gene associated with obesity, Nijenhuis et al. (2003) found that all the mutant receptors were poorly expressed at the cell surface and showed a decreased maximal response to agonist, indicating that the mutations impair receptor function. The findings supported the hypothesis that loss of function of MC4R contributes to obesity. </p><p>Hinney et al. (2003) performed a mutation screen of the coding region of the MC4R gene in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; 5 of these were novel. In vitro assays revealed that 9 of the 16 mutations led to impaired cAMP responses, compared with wildtype receptor constructs. The association test based on functionally relevant mutations was positive (p = 0.006, Fisher exact test, one-sided). They also screened a total of 1,040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (p = 0.033). The authors concluded that their results supported the hypothesis that these MC4R mutations represent major gene effects for obesity. </p><p>Santini et al. (2004) screened a population of Italian obese subjects for MC4R variants, demonstrating a 1.7% prevalence of potentially pathogenic mutations. They reported a novel heterozygous missense mutation that impaired MC4R functional activity in vitro. </p><p>Valli-Jaakola et al. (2004) screened 2 Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to 70% before age 10) and 252 morbidly obese adults (body mass index greater than 40 kg/m2) for MC4R mutations. They identified a pathogenic mutation (S127L; 155541.0021) in 1 child, causing severe early-onset obesity. They also identified a novel polymorphism in the coding region and 2 novel variations outside the coding region. </p><p>Hebebrand et al. (2004) compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations to wildtype controls. No significant differences in binge-eating episodes between carriers of the MC4R variants and wildtype controls were detected, and Hebebrand et al. (2004) concluded that binge-eating episodes are not a distinct feature of MC4R mutation carriers. This analysis was different from the study of Branson et al. (2003) because Hebebrand et al. (2004) studied only carriers of mutations that had been shown to be of functional relevance in vitro and did not include carriers of silent variants in the open reading frame, variants in untranslated regions (UTRs), or the val103-to-ile (V103I; 155541.0024) or I251L polymorphisms. </p><p>In a transmission/disequilibrium test on 520 trios with obesity, Geller et al. (2004) unexpectedly observed a lower transmission rate of the 103I allele (p = 0.017) in the MC4R gene. Metaanalysis of combined data from 7,713 individuals demonstrated a negative association of the 103I allele with obesity (odds ratio, 0.69; p = 0.03). Noting the apparent protective effect against obesity, the authors suggested that variation in the MC4R gene might entail both loss and gain of function. </p><p>By linear regression analysis of data from 2 large German population-based surveys with a total of 7,937 participants, Heid et al. (2005) found a significant decrease of 0.52 BMI units (p = 0.043) for heterozygous carriers of the V103I variant, which was observed in 3.7% of participants. Logistic regression analysis yielded a significantly negative association of the MC4R variant with above-average weight (odds ratio, 0.75; p = 0.017). Similar results were obtained in a comparison of obese (BMI greater than 30) to nonobese participants of either sex (odds ratio, 0.69; p = 0.026). The authors concluded that the V103I polymorphism could be regarded as contributing to polygenetically regulated body weight. </p><p>Lubrano-Berthelier et al. (2006) determined the prevalence of MC4R mutations in a cohort of severely obese adults and the clinical phenotype and the phenotype-genotype relationships of adult MC4R mutation carriers. The prevalence of obesity-specific MC4R mutations was 2.6% (95% CI = 1.5-3.7). The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%) and in patients with a later onset of the disease (2.35%). Adult obese MC4R mutation carriers did not present with binge eating or with any specific clinical phenotype. The authors concluded that the severity of the functional alterations of the mutated MC4Rs and, in particular, the intracellular retention of the receptor correlated with both the severity and the onset of obesity in the mutation carriers. </p><p>Hinney et al. (2006) investigated the prevalence and spectrum of MC4R mutations in 4,068 individuals of a German population-based study group (KORA-S4) and 1,003 German obese adults (BMI greater than 30 kg/m2). Sixteen (6 novel) coding nonsynonymous mutations were detected in 27 heterozygous individuals of KORA-S4. Four of the mutation alleles led to impaired receptor function in vitro; however, none of these 6 heterozygous mutation carriers was obese. In the obese adults, 6 coding nonsynonymous and a nonsense mutation were detected in 13 individuals. Only the nonsense mutation allele entailed impaired receptor function. The authors concluded that individuals heterozygous for nonsynonymous MC4R mutation alleles entailing impaired function were not obese and that nonsynonymous MC4R mutations causing impaired receptor function were rare in German obese adults (2 in 1,003 = 0.2%). </p><p>By direct sequencing of the coding region of the MC4R gene in a cohort of 289 Czech children and adolescents with early-onset obesity, Hainerova et al. (2007) found a prevalence of 2.4% of MC4R homozygous and heterozygous mutations. One novel variant (C84R) showed a significant reduction in cAMP signal properties of the MC4R. There was a similar response of MC4R mutation carriers and noncarriers to diet management. </p><p>In a genomewide association study of 318,237 SNPs for insulin resistance and related phenotypes in 2,684 Indian Asians and 11,955 individuals of Indian Asian or European ancestry, Chambers et al. (2008) found association between rs12970134, located near the MC4R gene, and waist circumference (p = 1.7 x 10(-9)). Homozygotes for the risk allele had an approximately 2 cm greater waist circumference compared to wildtype. The authors concluded that genetic variation near MC4R is associated with a risk of adiposity and insulin resistance. </p><p>Loos et al. (2008) performed a metaanalysis of data from 4 European population-based studies and 3 disease-case series, involving a total of 16,876 individuals of European descent, and found a significant association between rs17782313, located 188 kb downstream of the MC4R gene, and BMI in adults (p = 2.8 x 10(-15)) and children (p = 1.5 x 10(-8)). In case-control analyses, the odds for severe childhood obesity reached 1.30 (p = 8.0 x 10(-11)), and overtransmission of the risk allele to obese offspring was observed in 660 families. The authors concluded that common variants near the MC4R gene influence fat mass, weight, and obesity risk at the population level. </p><p>Willer et al. (2009) performed a metaanalysis of 15 genomewide association studies for BMI comprising 32,387 participants and followed up top signals in 14 additional cohorts comprising 59,082 participants. They strongly confirmed association with MC4R at SNP rs17782313 with a per-allele change in BMI of 0.20 and an overall P value of 1.1 x 10(-20). </p><p>Hardy et al. (2010) genotyped variants in FTO (610966; rs9939609) and near MC4R (rs17782313) in 1,240 men and 1,239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2-20 years) or adulthood (20-53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; P less than 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele), and then weakened during adulthood (-0.003 SDS/A-allele/year, p = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; p = 0.006), peaked at age 20 years (0.13 SDS/C-allele), and weakened during adulthood (-0.002 SDS/C-allele/year, p = 0.05). Hardy et al. (2010) concluded that genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. </p><p>Drabkin et al. (2018) tested 16 members of a large consanguineous Bedouin family, including 4 with autosomal recessive early-onset obesity, and identified a novel mutation (c.124G-T, E42X) in the MC4R gene that eliminated nearly all functional domains of the protein. The phenotype in homozygotes in this family was much more severe than in heterozygotes for the mutation, both with regard to degree of obesity and metabolic consequences (e.g., triglycerides). </p>
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<strong>Cytogenetics</strong>
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<p>It has been hypothesized that MC4R mutations found in association with obesity result in a loss of MC4R gene function due to haploinsufficiency. Cody et al. (1999) studied the molecular basis of the phenotype of individuals with large deletions of 18q. Because of its location at 18q21.3, the MC4R gene was hemizygous in approximately one-third of the individuals in this study. If hemizygosity of the MC4R gene results in haploinsufficiency-induced obesity, then individuals with deletion of 18q whose deletions included the MC4R gene should be obese in comparison with those individuals whose deletion did not include the gene. The data of Cody et al. (1999) indicated no difference in obesity among those deleted and not deleted for the gene. Thus, the MC4R gene product must be haplosufficient, and the involvement of MC4R in obesity may reflect a dominant-negative effect. </p><p>Heisler et al. (2002) found that genetic or pharmacologic blockade of MC4R and MC3R (155540) is sufficient to attenuate the anorectic efficacy of threshold doses of d-FEN (D-fenfluramine), suggesting that drugs targeting these downstream melanocortin pathways may act in part in a manner similar to d-FEN to decrease food intake and body weight with fewer side effects. </p>
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<strong>Animal Model</strong>
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<p>Huszar et al. (1997) found that inactivation of the melanocortin-4 receptor by gene targeting in mice resulted in a maturity-onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycinemia. This syndrome recapitulated several of the characteristic features of the 'agouti' syndrome, which results from ectopic expression of agouti protein (600201), a pigmentation factor normally expressed in the skin. The findings identified a novel signaling pathway in the mouse for body weight regulation and supported a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the melanocortin-4 receptor. </p><p>Marsh et al. (1999) found that the leptin resistance of obese Mc4r -/- mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF; 118945), corticotropin-releasing factor (CRF; 122560), or urocortin (UCN; 600945); or the orexigenic (appetite-stimulating) actions of neuropeptide Y (NPY; 162640) or peptide YY (PYY; 600781), indicating that these neuromodulators act independently or downstream of Mc4r signaling. Marsh et al. (1999) showed that homozygous Mc4r-deficient mice do not respond to the anorectic action of a melanocyte-stimulating hormone (MSH)-like agonist, suggesting that alpha-MSH (see 176830) inhibits feeding primarily by activating Mc4r. </p><p>Kim et al. (2000) studied MC4R as a candidate gene for the control of economically important growth and performance traits in the pig. They found a missense mutation in a region highly conserved among melanocortin receptor genes: a G-to-A transition at a position corresponding to human codon 298, changing GAU (asp) to AAU (asn). The asp298 allele was associated with less backfat thickness, slower growth rate, and lower feed intake. In an association study of this MC4R polymorphism in a large number of individual animals from several different pig lines, they found a significant association of MC4R genotypes with backfat, growth rate, and feed intake in a number of lines. The authors considered it likely that the variant amino acid residue of the MC4R mutation (or a closely linked mutation) causes a significant change of the MC4R function. </p><p>Chen et al. (2000) evaluated the potential role of MC3R in energy homeostasis by studying Mc3r-deficient (Mc3r -/-) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. Mice lacking both Mc3r and Mc4r became significantly heavier than Mc4r -/- mice. Chen et al. (2000) concluded that Mc3r and Mc4r serve nonredundant roles in the regulation of energy homeostasis. Cummings and Schwartz (2000) showed that these studies demonstrated that the 2 melanocortin receptor isoforms reduce body weight through distinct and complementary mechanisms. Mc4r regulates food intake and possibly energy expenditure, whereas Mc3r influences feed efficiency and the petitioning of fuel stores into fat. </p><p>Ste Marie et al. (2000) studied Mc4r-null mice to determine whether aberrant metabolism contributes to their late-onset obesity. The consumption of the null mice was restricted to (i.e., pair-fed with) that of wildtype mice. The null females maintained body weights intermediate to those of wildtype and nonpair-fed null females, whereas pair-feeding normalized the body weights of null male mice. These and other findings indicated that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in Mc3r-null mice. </p><p>By a combination of genetic, pharmacologic, and anatomic approaches, Van der Ploeg et al. (2002) showed that MC4R, implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence was based on several findings: a highly selective nonpeptide MC4R agonist augmented erectile activity initiated by electrical stimulation of the cavernous nerve in wildtype, but not Mc4r-null, mice; copulatory behavior was enhanced by administration of a selective MC4R agonist and was diminished in mice lacking Mc4r; RT-PCR- and non-PCR-based methods demonstrated MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, and pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and in situ hybridization of glans tissue from the human and rat penis revealed MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicated MC4R in the modulation of penile erectile function and provided evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. The results supported the existence of MC4R-controlled neuronal pathways that control sexual function. </p><p>Xu et al. (2003) found that, like MC4R mutants, mouse mutants that express decreased amounts of the brain-derived neurotrophic factor (BDNF; 113505) receptor TrkB (600456) showed hyperphagia and maturity-onset obesity, suggesting a role for BDNF in energy balance. The authors found that BDNF is an anorexigenic factor that is highly expressed in murine ventromedial hypothalamic (VMH) nuclei and is regulated by feeding status. Deficiency in MC4R signaling reduced expression of BDNF in the VMH, indicating that BDNF and its receptor TrkB are downstream components in the MC4R-mediated control of energy balance. </p><p>Balthasar et al. (2005) devised a strategy to target Mc4r reactivation in specific neurons in Mc4r-null mice. They found that restoration of Mc4r expression in the paraventricular hypothalamus and in a subpopulation of amygdala neurons prevented 60% of the obesity observed in Mc4r-null animals. Rescued animals reduced their food intake toward normal. However, measures of oxygen consumption suggested that their remaining obesity was due to low energy expenditure. Balthasar et al. (2005) concluded that different melanocortin pathways control food intake and energy expenditure. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>24 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 OBESITY (BMIQ20)</strong>
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MC4R, 4-BP DEL, NT631
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SNP: rs13447338,
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gnomAD: rs13447338,
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ClinVar: RCV000015392, RCV003407336
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<p>Yeo et al. (1998) identified a cohort of severely obese (BMIQ20; 618406) children in whom no evidence for a recognized clinical syndrome or a structural hypothalamic cause for their obesity was found. In 1 of 63 of these subjects screened for MC4R mutations, they identified heterozygosity for a 4-bp deletion at codon 211 of the MC4R gene. The deletion of CTCT resulted in a missing leucine and a frameshift that introduced a stop codon 5 amino acids downstream of the deletion. This disrupted the fifth transmembrane domain of the receptor and resulted in a truncated protein of 215 residues. The index patient was 4 years old and the only child of a nonconsanguineous union. Although his birthweight was 3.8 kg (50th centile), progressive weight gain led to a weight of 32 kg (more than 99th centile) at the age of 4 years. There was a history of hyperphagia with constant food seeking and distress when food was not provided. Fasting serum leptin concentration was appropriate for the degree of obesity. The mother was not obese and had a normal appetite. The father, aged 30 years, weighed 139 kg at a height of 185 cm. He was also of normal birth weight, but his weight began to deviate from predicted centiles at 6 months of age. He was found to be heterozygous for the same mutation. He had no sibs and no further information concerning his parents was available. </p><p>In a severely obese mother and daughter (BMIs of 37.5 and 42, respectively), Hinney et al. (1999) identified heterozygosity for the 4-bp deletion in the MC4R gene. </p>
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<span class="mim-font">
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<strong>.0002 OBESITY (BMIQ20)</strong>
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MC4R, 4-BP INS, NT732
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SNP: rs2143966223,
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ClinVar: RCV000015393
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<p>Vaisse et al. (1998) used PCR-SSCP with 5 primer pairs covering the entire single exon of MC4R to screen for mutations in 43 individuals with morbid obesity (BMIQ20; 618406). A single patient was found to have heterozygosity for a frameshift mutation, a 4-bp insertion at nucleotide 732 resulting in expression of a nonfunctional, truncated receptor lacking the sixth and seventh transmembrane domains. The patient was a 35-year-old woman with obesity that developed in infancy. Her birth weight was normal. Her weight was 45 kg with a height of 141 cm at age 10 years, and 80 kg with a height of 163 cm at age 20. Blood glucose and plasmid lipid levels were normal; serum leptin levels were consistent with her adiposity. She belonged to a large family of obese subjects: her mother, sister, niece, and a younger brother were also obese. </p>
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<span class="mim-font">
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<strong>.0003 OBESITY (BMIQ20)</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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MC4R, TYR35TER AND ASP37VAL
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<br />
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SNP: rs13447324, rs13447325,
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|
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gnomAD: rs13447324, rs13447325,
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ClinVar: RCV000015394, RCV000015395, RCV000202583, RCV000255005, RCV000435394, RCV001174507, RCV001262822, RCV001699179, RCV002504792, RCV004017247, RCV004797761
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 obese (BMIQ20; 618406) probands (BMI, 31.29 kg/m2 and 45.91 kg/m2, respectively), Hinney et al. (1999) identified a C-to-A transversion at nucleotide 105 of the MC4R gene, resulting in a tyr35-to-ter substitution. This mutation led to a truncated protein that encompassed the N-terminal extracellular domain. Both carriers also showed an A-to-T transversion at nucleotide 110, resulting in an asp37-to-val substitution. In both cases these mutations were maternally transmitted, indicating they form a haplotype. </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-text-font">
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<strong>.0004 MOVED TO 155541.0003</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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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 OBESITY (BMIQ20)</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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MC4R, VAL50MET
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<br />
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SNP: rs121913557,
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gnomAD: rs121913557,
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ClinVar: RCV000015396, RCV004760334
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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 child with severe obesity (BMIQ20; 618406) child, Dubern et al. (2001) identified a G-to-A transition at nucleotide 148 of the MC4R gene, resulting in a valine-to-methionine substitution at codon 50 in the first transmembrane domain of the melanocortin-4 receptor. This mutation was found in heterozygosity in this patient and was not identified in any of the 283 nonobese adults. </p><p>In time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment, Lotta et al. (2019) observed loss-of-function effects with the V50M mutant in the beta-arrestin-mediated signaling assay, whereas the mutant showed similar effects to wildtype MC4R in the cAMP assay. </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>.0006 OBESITY (BMIQ20)</strong>
|
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</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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MC4R, SER58CYS
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<br />
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|
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SNP: rs121913558,
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gnomAD: rs121913558,
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ClinVar: RCV000015397
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|
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|
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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 1 of 63 obese (BMIQ20; 618406) children screened for mutations of MC4R, Dubern et al. (2001) identified heterozygosity for an A-to-T transversion at nucleotide 172 of the MC4R gene, resulting in a ser-to-cys substitution at codon 58 in the first transmembrane domain of the melanocortin-4 receptor. This mutation was not identified in any of 283 nonobese adults. The proband's sister, who was also heterozygous for the mutation, had a BMI within the normal range for her age. </p>
|
|
</span>
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</div>
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|
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<div>
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|
<br />
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</div>
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|
|
</div>
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|
<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 OBESITY (BMIQ20)</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
|
MC4R, ILE102SER
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|
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<br />
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|
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SNP: rs121913559,
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|
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gnomAD: rs121913559,
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|
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|
|
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ClinVar: RCV000015398
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 63 obese (BMIQ20; 618406) children, Dubern et al. (2001) identified heterozygosity for a T-to-G transversion at nucleotide 305 of the MC4R gene, resulting in an isoleucine-to-serine substitution at codon 102 in the second transmembrane domain of the melanocortin-4 receptor. The proband's mother, who was also heterozygous for the mutation, was of normal weight and had no history of obesity. </p><p>Through detailed functional characterization of cell surface expression, ligand binding, and signaling properties, Tao and Segaloff (2005) determined that the I102T variant results in loss of function of the MC4R protein. </p>
|
|
</span>
|
|
</div>
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|
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|
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<div>
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<br />
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|
</div>
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|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, ILE170VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913560,
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|
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|
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gnomAD: rs121913560,
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|
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|
|
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ClinVar: RCV000015399, RCV003407337, RCV003546455
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 63 obese (BMIQ20; 618406) children, Dubern et al. (2001) identified an A-to-G transition at nucleotide 508 of the MC4R gene, resulting in an isoleucine-to-valine substitution at codon 170 in the fourth transmembrane domain of the melanocortin-4 receptor. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, ASN274SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913561,
|
|
|
|
|
|
gnomAD: rs121913561,
|
|
|
|
|
|
ClinVar: RCV000015400, RCV001125885, RCV001531447, RCV003892108
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Mergen et al. (2001) determined the nucleotide sequence of the entire coding region of the MC4R gene in 40 morbidly obese (BMIQ20; 618406) subjects from independent families. The authors reported a novel heterozygous mutation, asn274 to ser (N274S), in an obese female (age, 52 years; height, 158 cm; weight, 104 kg; BMI, 41.7 kg/m2). The sister of the proband (age, 55 years; height, 160 cm; weight, 110 kg; BMI, 43 kg/m2) carried the same mutation. Although both sisters were morbidly obese and hypertensive, the proband had normal plasma insulin and fasting blood glucose levels, whereas her sister had type II diabetes mellitus (125853). No abnormalities of the reproductive function were present. Despite marked hyperphagia in childhood, both sisters had a history of relatively diminished intensity of appetite after the age of 20. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, 1-BP INS, 112A
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000015401
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband and his mother and sister, all with early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) identified heterozygosity for a frameshift mutation in the MC4R gene, 112insA, which resulted in complete loss of activity of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, 4-BP DEL, 211CTCT
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000015392, RCV003407336
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son with early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) identified heterozygosity for a frameshift mutation in the MC4R gene, 211delCTCT, which resulted in complete loss of activity of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, 2-BP INS, 279GT
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000015403
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In each of 2 presumably unrelated families, Farooqi et al. (2003) found that the father and 1 child with early-onset obesity (BMIQ20; 618406) were heterozygous for a frameshift mutation in the MC4R gene, 279insGT, which resulted in complete loss of activity of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, ILE125LYS
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000015404, RCV004748522
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In each of 2 presumably unrelated families, Farooqi et al. (2003) found that a parent and 1 child with early-onset obesity (BMIQ20; 618406) were heterozygous for an ile125-to-lys (I125K) mutation in the MC4R gene. The protein showed no activity on in vitro assay. </p><p>Yeo et al. (2003) demonstrated that the I125K mutation was completely unable to generate cAMP in response to ligand. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, CYS271TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913562,
|
|
|
|
|
|
gnomAD: rs121913562,
|
|
|
|
|
|
ClinVar: RCV000015405, RCV000768578, RCV004017248, RCV004748523
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with early-onset obesity (BMIQ20; 618406) in 8 individuals in 3 successive generations, Farooqi et al. (2003) found that affected individuals were heterozygous for a cys271-to-tyr (C271Y) mutation in the MC4R gene. The protein showed no activity on in vitro assay. </p><p>Yeo et al. (2003) observed that the C271Y mutation was completely unable to generate cAMP in response to ligand and showed impaired cell surface expression. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, ALA175THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913563,
|
|
|
|
|
|
gnomAD: rs121913563,
|
|
|
|
|
|
ClinVar: RCV000015406, RCV000768579, RCV002247343, RCV002513063, RCV003415708
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son with early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) found heterozygosity for an ala175-to-thr (A175T) mutation in the MC4R gene. The protein showed partial activity on in vitro assay. </p><p>In time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment, Lotta et al. (2019) observed loss-of-function effects with the A175T mutant compared to wildtype MC4R. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, ILE316SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913564,
|
|
|
|
|
|
gnomAD: rs121913564,
|
|
|
|
|
|
ClinVar: RCV000015407, RCV000778539, RCV004017249
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family in which there was extensive consanguinity, Farooqi et al. (2003) found that early-onset obesity (BMIQ20; 618406) in 6 individuals in 2 generations was associated with heterozygosity for an ile316-to-ser (I316S) mutation in the MC4R gene. In a second, unrelated family, the authors found that early-onset obesity in a mother and 3 daughters was associated with this mutation. The protein showed partial activity on in vitro assay in both families. </p><p>Yeo et al. (2003) observed that the I316S mutant protein showed reduced affinity for alpha-MSH (see 176830), but retained normal affinity for the antagonist agouti-related protein (AGRP; 602311). </p><p>In time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment, Lotta et al. (2019) observed loss-of-function effects with the I316S mutant compared to wildtype MC4R. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 OBESITY (BMIQ20)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MC4R, TYR287TER
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<br />
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SNP: rs121917829,
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ClinVar: RCV000015408, RCV004017250
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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 early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) found homozygosity for a tyr287-to-ter (Y287X) mutation in the MC4R gene; the mother and a sister were also obese but were heterozygous for the mutation. On in vitro assay, the protein showed no activity. </p><p>Yeo et al. (2003) demonstrated that the Y287X mutation showed impaired cell surface expression. </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>.0018 OBESITY (BMIQ20)</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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MC4R, ASN97ASP
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<br />
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SNP: rs121913565,
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ClinVar: RCV000015409
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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 early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) found homozygosity for an asn97-to-asp (N97D) mutation in the MC4R gene; her consanguineous parents and a sister were also obese but were heterozygous for the mutation. On in vitro assay, the protein showed no activity. </p><p>Yeo et al. (2003) demonstrated that the N97D mutation was completely unable to generate cAMP in response to ligand. </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>.0019 OBESITY (BMIQ20)</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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MC4R, ASN62SER
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<br />
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SNP: rs121913566,
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gnomAD: rs121913566,
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ClinVar: RCV000015410, RCV004017251
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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 an inbred family in which 10 individuals in 3 generations had early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) found that the proband and 4 of his cousins were homozygous for an asn62-to-ser (N62S) mutation in the MC4R gene. The consanguineous parents in each case were heterozygous for the mutation and showed obesity that was less severe. On in vitro assay, the protein showed partial activity. </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>.0020 OBESITY (BMIQ20)</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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MC4R, 15-BP DEL
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<br />
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SNP: rs777077280,
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gnomAD: rs777077280,
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ClinVar: RCV000015411
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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 female patient with onset of obesity (BMIQ20; 618406) at less than 5 years of age, Donohoue et al. (2003) detected an in-frame deletion in the MC4R gene of codons 88 through 92 (delta88-92). These codons were predicted to lie within the second transmembrane domain. Functional analysis revealed that the mutant receptor was expressed well on the cell surface but was completely devoid of ligand binding and cAMP generation in response to agonist stimulation. </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>.0021 OBESITY (BMIQ20)</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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MC4R, SER127LEU
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<br />
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SNP: rs13447331,
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gnomAD: rs13447331,
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ClinVar: RCV000015412, RCV000414065, RCV000768580, RCV004017252, RCV004748524
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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 14.8-year-old boy with severe early-onset obesity (BMIQ20; 618406), Valli-Jaakola et al. (2004) identified a ser127-to-leu (S127L) mutation in the melanocortin-4 receptor. Abnormal weight gain began in the second year of life. The patient presented with acanthosis nigricans in the neck and axillae and demonstrated marked hyperinsulinemia during an oral glucose tolerance test despite normal glucose tolerance. Blood pressure was normal for age. His father, in whom the same mutation was found, suffered form severe obesity in childhood although the phenotype became less apparent in adulthood. Functional studies in transiently transfected 239T cells indicated that signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma-1-MSH (see 176830) were impaired. Valli-Jaakola et al. (2004) noted that this mutation had been reported by Lubrano-Berthelier et al. (2003) and Hinney et al. (2003) in a total of 4 patients. </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>.0022 OBESITY (BMIQ20)</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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MC4R, 2-BP DEL, 750GA
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<br />
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SNP: rs13447339,
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gnomAD: rs13447339,
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ClinVar: RCV000015413, RCV000500812, RCV001249014, RCV002510907, RCV003935293
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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 an obese (BMIQ20; 618406) child of first-cousin parents of North African origin, Lubrano-Berthelier et al. (2004) detected a homozygous 2-bp deletion in the MC4R gene (delta750-751GA). MC4R activity was completely absent. The parents and all sibs of the proband were heterozygous for the mutation. Lubrano-Berthelier et al. (2004) compared the clinical and endocrine characteristics of this patient with those observed in leptin receptor (601007)-deficient patients. They concluded that in humans, the MC4R mediates most of the anorectic effects of leptin (164160) in early childhood. In contrast, MC4R does not mediate the effect of leptin on linear growth and other endocrine axes. In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia. </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>.0023 OBESITY (BMIQ20)</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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|
MC4R, ALA219VAL
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<br />
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SNP: rs121913567,
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gnomAD: rs121913567,
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ClinVar: RCV000015414, RCV004748525
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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 a study of the MC4R gene in 750 Danish men with juvenile-onset obesity (BMIQ20; 618406) and 706 control subjects, Larsen et al. (2005) detected a novel missense mutation in 1 subject, ala219 to val (A219V), that arose from a 656C-T transition. The A219V variant showed significant impairment of cAMP-induced activity in response to melanotan II (MTII) compared with the wildtype receptor (34%). </p><p>In time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment, Lotta et al. (2019) observed loss-of-function effects with the A219V mutant in the cAMP assay, whereas the mutant showed similar effects to wildtype MC4R in the beta-arrestin-mediated signaling assay. </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>.0024 MC4R POLYMORPHISM</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
OBESITY, RESISTANCE TO, INCLUDED
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
MC4R, VAL103ILE ({dbSNP rs2229616})
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<br />
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SNP: rs2229616,
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gnomAD: rs2229616,
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ClinVar: RCV000202600, RCV000445452, RCV000768671, RCV000768672, RCV001699064, RCV001778791, RCV002057039, RCV003977552
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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>Gotoda et al. (1997) sequenced the MC4R gene in 40 morbidly obese white British men with body mass indexes (BMIs) greater than 35, and 10 lean men with BMIs less than 18, and identified heterozygosity for a 307G-A transition, resulting in a val103-to-ile (V103I) substitution in 2 obese men. No other nucleotide alterations were found. The prevalence of the V103I missense variant was then studied in 322 white British men from a population-based epidemiologic survey, including 190 men with BMI greater than 28 and 132 men with BMI less than 22. No homozygotes for V103I were identified, and the frequency of heterozygosity for the V103I substitution was similar between the 2 groups (4.2% and 4.5%). In addition, there was no significant difference in BMI, total skinfold thickness, or plasma insulin and glucose levels between heterozygotes and V103 homozygotes. The authors concluded that coding sequence mutations in MC4R were unlikely to be a major cause of human obesity. </p><p>Using SSCP analysis, Gu et al. (1999) screened the entire MC4R coding region in 190 individuals of various body sizes and identified heterozygosity for the V103I allele in 7 subjects, including 4 (3.6%) of 110 who were extremely obese (BMI greater than 50), 1 (3.3%) of 30 who were obese (BMI between 30 and 50), none of 3 who were intermediate (BMI greater than 25), and 2 (4.3%) of 47 who were lean (BMI less than 25). Functional analysis of the V103I variant in both stably and transiently transfected 293 cells showed dose-response patterns upon activation by melanocortin peptides that were not significantly different from those of wildtype MC4R. </p><p>Hinney et al. (1999) screened the coding region of the MC4R gene in 306 extremely obese children and adolescents (mean BMI, approximately 34.4), 25 healthy underweight students (mean BMI, approximately 17), 52 normal-weight students (mean BMI, 22), 51 inpatients with anorexia nervosa (mean BMI, approximately 14), and 27 patients with bulimia nervosa (mean BMI, approximately 22). The V103I variant was detected at similar frequencies in all groups, confirming the findings of Gotoda et al. (1997). </p><p><strong><em>Obesity, Resistance to</em></strong></p><p>
|
|
In a transmission/disequilibrium test on 520 trios with obesity, Geller et al. (2004) unexpectedly observed a lower transmission rate of the 103I allele (p = 0.017) (see 618406). Metaanalysis of combined data from 7,713 individuals, primarily samples of European origin, in 2 large case-control studies and 12 published studies demonstrated a negative association of the 103I allele with obesity (odds ratio, 0.69; p = 0.03). Additional screening of 4 other ethnic groups (Tanzanians, African Americans, Chinese, and Japanese) showed 103I frequencies ranging from 0 to 6.5%. Functional analysis in COS-7 cells transiently transfected with the V103I mutant or wildtype MC4R revealed similar cAMP levels at baseline, with no consistent differences in maximum or EC50 values after stimulation with 3 agonists, and the binding properties of the mutant and wildtype proteins were also indistinguishable. Noting the apparent protective effect against obesity, the authors suggested that variation in the MC4R gene might entail both loss and gain of function. </p><p>Heid et al. (2005) analyzed data from 2 large German population-based surveys with a total of 7,937 participants. By linear regression, they found a significant decrease of 0.52 BMI units (p = 0.043) for heterozygous carriers of the V103I variant, which was observed in 3.7% of participants. Logistic regression analysis yielded a significantly negative association of the MC4R variant with above-average weight (odds ratio, 0.75; p = 0.017). Similar results were obtained in a comparison of obese (BMI greater than 30) to nonobese participants of either sex (odds ratio, 0.69; p = 0.026). The authors concluded that the V103I polymorphism could be regarded as contributing to polygenetically regulated body weight. </p><p>In a study of 452,300 participants of European ancestry from the UK Biobank database, Lotta et al. (2019) found that the V103I variant was the most common nonsynonymous variant (allele frequency, 2%). Time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment showed gain-of-function effects with the V103I variant, which exhibited significant bias towards beta-arrestin-mediated signaling. Previously reported associations of V103I with lower BMI and obesity risk were confirmed in this analysis. In metaanalyses of genetic association studies involving more than 600,000 individuals, V103I was associated with lower risk of type 2 diabetes (p = 7 x 10(-7)) and of coronary artery disease (p = 0.003), as well as with lower diastolic blood pressure and resting heart rate. Functional analysis showed that the magnitude and duration of ligand-induced ERK1/2 phosphorylation was also increased (p = 0.009). Confocal microscopy of transfected COS-7 cells demonstrated that whereas wildtype MC4R translocated from the membrane into the cytoplasm upon agonist stimulation, the V103I mutant remained at the cell surface. Fluorescence-activated cell-sorting assay of transfected HeLa cells showed a 23% reduction in cell surface expression of wildtype MC4R upon ligand stimulation, whereas there was no change in V103I expression. </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>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Balthasar, N., Dalgaard, L. T., Lee, C. E., Yu, J., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R. A., Kenny, C. D., Christiansen, L. M., Edelstein, E., Choi, B., Boss, O., Aschkenasi, C., Zhang, C., Mountjoy, K., Kishi, T., Elmquist, J. K., Lowell, B. B.
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<strong>Divergence of melanocortin pathways in the control of food intake and energy expenditure.</strong>
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Cell 123: 493-505, 2005.
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[PubMed: 16269339]
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[Full Text: https://doi.org/10.1016/j.cell.2005.08.035]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Branson, R., Potoczna, N., Kral, J. G., Lentes, K.-U., Hoehe, M. R., Horber, F. F.
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<strong>Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.</strong>
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|
New Eng. J. Med. 348: 1096-1103, 2003.
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[PubMed: 12646666]
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[Full Text: https://doi.org/10.1056/NEJMoa021971]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Brocke, K. S., Neu-Yilik, G., Gehring, N. H., Hentze, M. W., Kulozik, A. E.
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|
<strong>The human intronless melanocortin 4-receptor gene is NMD insensitive.</strong>
|
|
Hum. Molec. Genet. 11: 331-335, 2002.
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[PubMed: 11823452]
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[Full Text: https://doi.org/10.1093/hmg/11.3.331]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chambers, J. C., Elliott, P., Zabaneh, D., Zhang, W., Li, Y., Froguel, P., Balding, D., Scott, J., Kooner, J. S.
|
|
<strong>Common genetic variation near MC4R is associated with waist circumference and insulin resistance.</strong>
|
|
Nature Genet. 40: 716-718, 2008.
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|
[PubMed: 18454146]
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[Full Text: https://doi.org/10.1038/ng.156]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Chen, A. S., Marsh, D. J., Trumbauer, M. E., Frazier, E. G., Guan, X.-M., Yu, H., Rosenblum, C. I., Vongs, A., Feng, Y., Cao, L., Metzger, J. M., Strack, A. M., and 9 others.
|
|
<strong>Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.</strong>
|
|
Nature Genet. 26: 97-102, 2000.
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|
[PubMed: 10973258]
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[Full Text: https://doi.org/10.1038/79254]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cody, J. D., Reveles, X. T., Hale, D. E., Lehman, D., Coon, H., Leach, R. J.
|
|
<strong>Haplosufficiency of the melanocortin-4 receptor gene in individuals with deletions of 18q.</strong>
|
|
Hum. Genet. 105: 424-427, 1999.
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[PubMed: 10598807]
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[Full Text: https://doi.org/10.1007/s004390051125]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cummings, D. E., Schwartz, M. W.
|
|
<strong>Melanocortins and body weight: a tale of two receptors.</strong>
|
|
Nature Genet. 26: 8-9, 2000.
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|
[PubMed: 10973234]
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[Full Text: https://doi.org/10.1038/79223]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Donohoue, P. A., Tao, Y.-X., Collins, M., Yeo, G. S. H., O'Rahilly, S., Segaloff, D. L.
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Sonja A. Rasmussen - updated : 08/28/2020<br>Ada Hamosh - updated : 06/26/2020<br>Marla J. F. O'Neill - updated : 05/01/2019<br>Bao Lige - updated : 08/06/2018<br>Ada Hamosh - updated : 05/15/2017<br>Ada Hamosh - updated : 06/23/2015<br>Patricia A. Hartz - updated : 2/7/2014<br>Ada Hamosh - updated : 8/29/2012<br>Ada Hamosh - updated : 8/8/2011<br>George E. Tiller - updated : 1/5/2011<br>Ada Hamosh - updated : 1/15/2010<br>Marla J. F. O'Neill - updated : 7/16/2008<br>John A. Phillips, III - updated : 3/31/2008<br>John A. Phillips, III - updated : 7/16/2007<br>John A. Phillips, III - updated : 7/16/2007<br>John A. Phillips, III - updated : 5/14/2007<br>John A. Phillips, III - updated : 4/4/2006<br>John A. Phillips, III - updated : 7/26/2005<br>John A. Phillips, III - updated : 7/6/2005<br>John A. Phillips, III - updated : 4/29/2005<br>John A. Phillips, III - updated : 4/19/2005<br>George E. Tiller - updated : 4/19/2005<br>John A. Phillips, III - updated : 4/11/2005<br>John Logan Black, III - updated : 3/2/2005<br>George E. Tiller - updated : 10/26/2004<br>Cassandra L. Kniffin - updated : 6/24/2003<br>Cassandra L. Kniffin - updated : 6/16/2003<br>Victor A. McKusick - updated : 4/17/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Victor A. McKusick - updated : 3/20/2003<br>Victor A. McKusick - updated : 10/9/2002<br>George E. Tiller - updated : 9/23/2002<br>Ada Hamosh - updated : 8/7/2002<br>John A. Phillips, III - updated : 3/13/2002<br>Ada Hamosh - updated : 9/24/2001<br>Victor A. McKusick - updated : 11/27/2000<br>Victor A. McKusick - updated : 8/30/2000<br>Victor A. McKusick - updated : 3/15/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Victor A. McKusick - updated : 12/6/1999<br>Victor A. McKusick - updated : 12/23/1998<br>Carol A. Bocchini - updated : 11/17/1998<br>Victor A. McKusick - updated : 9/23/1998<br>Victor A. McKusick - updated : 2/7/1997
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Thank you in advance for your generous support, <br />
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