3541 lines
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Entry
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- *152760 - GONADOTROPIN-RELEASING HORMONE 1; GNRH1
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- OMIM
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<p>
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<span class="h4">*152760</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/152760">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div 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=ENSG00000147437;t=ENST00000421054" 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=2796" 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=152760" 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=ENSG00000147437;t=ENST00000421054" 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_000825,NM_001083111" 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_001083111" 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=152760" 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=08860&isoform_id=08860_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/GNRH1" 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/31956,34357,121522,386749,116496759,116496903,119583995,119583996,133908612,395394022" 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/P01148" 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=2796" 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=ENSG00000147437;t=ENST00000421054" 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=GNRH1" 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=GNRH1" 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+2796" 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/GNRH1" 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:2796" 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/2796" 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=chr8&hgg_gene=ENST00000421054.7&hgg_start=25419258&hgg_end=25425040&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:4419" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=152760[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 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=152760[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000147437" 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=GNRH1" 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=GNRH1" 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=GNRH1" 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=GNRH1&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/PA28798" 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:4419" 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:95789" 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/GNRH1#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:95789" 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/2796/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2796" 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>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2796" 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=GNRH1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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152760
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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GONADOTROPIN-RELEASING HORMONE 1; GNRH1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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GNRH<br />
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LUTEINIZING HORMONE-RELEASING HORMONE; LHRH
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</span>
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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PROLACTIN RELEASE-INHIBITING FACTOR, INCLUDED; PIF, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GNRH1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GNRH1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/8/139?start=-3&limit=10&highlight=139">8p21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:25419258-25425040&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'})">8:25,419,258-25,425,040</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/8/139?start=-3&limit=10&highlight=139">
|
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8p21.2
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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?Hypogonadotropic hypogonadism 12 with or without anosmia
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
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</span>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/614841"> 614841 </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/152760" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/152760" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
|
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<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
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<p>Luteinizing hormone-releasing hormone (LHRH), a decapeptide, is a key molecule in the hypothalamic-pituitary-gonadal axis that controls human reproduction. It is produced by hypothalamic neurons, secreted in a pulsatile manner into the capillary plexus of the median eminence, and effects the release of luteinizing hormone and follicle-stimulating hormone from gonadotropic cells of the anterior pituitary. <a href="#22" class="mim-tip-reference" title="Seeburg, P. H., Adelman, J. P. <strong>Characterization of cDNA for precursor of human luteinizing hormone releasing hormone.</strong> Nature 311: 666-668, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6090951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6090951</a>] [<a href="https://doi.org/10.1038/311666a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6090951">Seeburg and Adelman (1984)</a> isolated cloned genomic and cDNA encoding the precursor of LHRH. These DNA sequences code for a protein of 92 amino acids in which the LHRH decapeptide is preceded by a signal peptide of 23 amino acids and followed by a gly-lys-arg sequence as expected for enzymatic cleavage of the decapeptide from its precursor and amidation of the C terminus of LHRH. LHRH, also referred to as 'gonadotropin-releasing hormone' (GNRH), and prolactin release-inhibiting factor (PIF) are derived from the same 92-amino acid precursor protein, which is encoded by a single gene. (PIF has also been used as the symbol for a parotid salivary protein; see <a href="/entry/168730">168730</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6090951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Hayflick, J. S., Adelman, J. P., Seeburg, P. H. <strong>The complete nucleotide sequence of the human gonadotropin-releasing hormone gene.</strong> Nucleic Acids Res. 17: 6403-6404, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2671939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2671939</a>] [<a href="https://doi.org/10.1093/nar/17.15.6403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2671939">Hayflick et al. (1989)</a> reported the complete nucleotide sequence of the GNRH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2671939" 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="#2" class="mim-tip-reference" title="Adelman, J. P., Mason, A. J., Hayflick, J. S., Seeburg, P. H. <strong>Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat.</strong> Proc. Nat. Acad. Sci. 83: 179-183, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2867548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2867548</a>] [<a href="https://doi.org/10.1073/pnas.83.1.179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2867548">Adelman et al. (1986)</a> determined that the GNRH genes of man and rat have a similar arrangement of 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2867548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The GNRH1 gene is exclusively expressed in a discrete population of neurons in the hypothalamus. To explore the protein-DNA interactions that occur within the GNRH1 promoter and the role of these interactions in targeting GNRH1 gene expression, <a href="#12" class="mim-tip-reference" title="Eraly, S. A., Nelson, S. B., Huang, K. M., Mellon, P. L. <strong>Oct-1 binds promoter elements required for transcription of the GnRH gene.</strong> Molec. Endocr. 12: 469-481, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9544983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9544983</a>] [<a href="https://doi.org/10.1210/mend.12.4.0092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9544983">Eraly et al. (1998)</a> mutagenized individual binding sites in the proximal promoter of the GNRH1 gene. DNAase I protection experiments revealed that footprint-2, a 51-bp sequence that confers a 20-fold induction of the GNRH1 gene, is composed of at least 3 independent protein-binding sites. Mutations in footprint-4 also decreased GNRH1 gene expression. Mobility shift cross-competition and antibody shift experiments demonstrated that OCT1 (<a href="/entry/602607">602607</a>) binds the octamer motifs within footprints-2 and -4. <a href="#12" class="mim-tip-reference" title="Eraly, S. A., Nelson, S. B., Huang, K. M., Mellon, P. L. <strong>Oct-1 binds promoter elements required for transcription of the GnRH gene.</strong> Molec. Endocr. 12: 469-481, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9544983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9544983</a>] [<a href="https://doi.org/10.1210/mend.12.4.0092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9544983">Eraly et al. (1998)</a> concluded that OCT1 plays a critical role in the regulation of GNRH1 transcription, binding functional elements in both the distal enhancer and the proximal promoter conserved region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9544983" 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="Wolfe, A., Kim, H. H., Tobet, S., Stafford, D. E. J., Radovick, S. <strong>Identification of a discrete promoter region of the human GnRH gene that is sufficient for directing neuron-specific expression: a role for POU homeodomain transcription factors.</strong> Molec. Endocr. 16: 435-449, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875100</a>] [<a href="https://doi.org/10.1210/mend.16.3.0780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11875100">Wolfe et al. (2002)</a> used a transgenic mouse model to isolate cis-regulatory elements important for directing gene expression to Gnrh neurons in the hypothalamus. Cell-specific expression, with the criterion being luciferase expression directed to Gnrh neurons of the hypothalamus, was observed when 992 bp, but not 795 bp, of the human GNRH1 gene promoter were used. Tissue-specific expression was also observed when a deletion construct containing the region from -992 to -763 was fused to a minimal 48-bp promoter fragment fused to a luciferase reporter gene. These data indicate that the region between -992 and -795 contains elements both essential and sufficient for targeting gene expression to Gnrh neurons. This promoter region contains 2 DNA binding sites for the POU class of transcription factors, each of which specifically interacted with the POU homeodomain proteins Brn2 (<a href="/entry/600494">600494</a>) and Oct1. Functional studies demonstrated that Brn2 increased promoter activity of the human and mouse GNRH1 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875100" 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>Neuron-specific expression of the GNRH1 gene is dependent on an upstream multicomponent enhancer. This enhancer is functional in a small population of GNRH1-producing hypothalamic neurons which, through the secretion of GNRH1, mediates central nervous system control of reproductive function. GNRH1 enhancer function requires activation by the GATA family of transcription factors that act through tandem consensus GATA-binding motifs, termed GATA-A and GATA-B. See GATA4 (<a href="/entry/600576">600576</a>). <a href="#17" class="mim-tip-reference" title="Lawson, M. A., Buhain, A. R., Jovenal, J. C., Mellon, P. L. <strong>Multiple factors interacting at the GATA sites of the gonadotropin-releasing hormone neuron-specific enhancer regulate gene expression.</strong> Molec. Endocr. 12: 364-377, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9514154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9514154</a>] [<a href="https://doi.org/10.1210/mend.12.3.0082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9514154">Lawson et al. (1998)</a> showed that 2 newly identified DNA-binding factors, which they referred to as GBF-A1/A2 and GBF-B1, bind the GNRH1 enhancer at sites overlapping the GATA factor-binding motifs. In vitro bindings of GATA, GBF-A1/A2, and GBF-B1 to the GNRH1 enhancer sequences occurred independently. Utilizing a GNRH1-expressing neuronal cell line as a model system, they showed by transient transfection that GBF-B1 is necessary for enhancer activity and independently activates the GNRH1 promoter. Transactivation of the GNRH1 enhancer in GT1 cells and in NIH 3T3 cells by GATA4 was modulated by GBF-B1 binding, suggesting that GBF-B1 interferes with GATA factor binding through a steric mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9514154" 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="Dong, K.-W., Yu, K.-L., Chen, Z.-G., Chen, Y.-D., Roberts, J. L. <strong>Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene.</strong> Endocrinology 138: 2754-2762, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9202214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9202214</a>] [<a href="https://doi.org/10.1210/endo.138.7.5249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9202214">Dong et al. (1997)</a> localized 4 specific nuclear protein-binding elements in the human GNRH1 upstream promoter. To test whether these 4 elements are reproductive tissue-specific, <a href="#10" class="mim-tip-reference" title="Dong, K.-W., Zheng, H.-M., Wen, Z.-Y., Chen, Z.-G. <strong>The POU homeodomain protein Oct-1 binds cis-regulatory element essential for the human GnRH upstream promoter activity in the JEG-3 cells.</strong> J. Clin. Endocr. Metab. 86: 2838-2844, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397896</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397896">Dong et al. (2001)</a> placed the 4 elements upstream to a thymidine kinase (<a href="/entry/188300">188300</a>) promoter/luciferase reporter gene and transfected the constructs into human placental choriocarcinoma (JEG-3) cells. Deletion of element 4 (E4, -987/-968) significantly decreased (4-fold) the luciferase activity. Further deletion of the other elements (E3, -960/-940 or E3 and E2 in combination, -919/-896) only slightly decreased the luciferase activity. In contrast, deletion of element 1 (E1, -876/-851) caused a 2-fold loss of luciferase activity and elimination of E2 and E3 only lost less than 2-fold of the luciferase activity. Furthermore, E4 DNA-protein complex was supershifted by antibodies against octamer-binding transcription factor-1 (OCT1), indicating that OCT1 binds to E4. The authors concluded that all 4 elements are required to confer tissue-specific expression of the GNRH1 gene in JEG-3 cells; however, E4 is the most important for the tissue-specific expression of the GNRH1 gene in JEG-3 cells. OCT1 factor binds with E4 and may be involved in the mediation of the human GNRH1 upstream promoter activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9202214+11397896" 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="Duan, W. R., Ito, M., Park, Y., Maizels, E. T., Hunzicker-Dunn, M., Jameson, J. L. <strong>GnRH regulates early growth response protein 1 transcription through multiple promoter elements.</strong> Molec. Endocr. 16: 221-233, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11818496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11818496</a>] [<a href="https://doi.org/10.1210/mend.16.2.0779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11818496">Duan et al. (2002)</a> examined the regulatory elements and signal transduction pathways by which GNRH regulates Egr1 (<a href="/entry/128990">128990</a>) transcription. Deletion analysis of the murine Egr1 promoter identified 2 regions (-370 to -342 and -116 to -73) that are critical for GNRH responsiveness in alpha-T3 pituitary gonadotrope cells. The first region, which contains 2 serum response elements (SREs), contributed about 70 to 80% of GNRH inducibility, whereas the second region, which contains 2 SREs and 1 Ets binding site, conferred an additional 20 to 30% of activity. Using specific protein kinase inhibitors, GNRH stimulation of Egr1 expression was found to be dependent on PKC/ERK pathways (see <a href="/entry/603607">603607</a>). The authors concluded that GNRH stimulation of Egr1 gene expression requires several distinct SREs/Ets elements and a cAMP response element and is mediated via activation of PKC/ERK signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11818496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Gnrh gene is expressed exclusively in a highly restricted population of approximately 800 neurons in the mediobasal hypothalamus in the mouse. The Otx2 homeoprotein (<a href="/entry/600037">600037</a>) colocalizes with Gnrh in embryonic mouse brain. <a href="#16" class="mim-tip-reference" title="Kelley, C. G., Lavorgna, G., Clark, M. E., Boncinelli, E., Mellon, P. L. <strong>The Otx2 homeoprotein regulates expression from the gonadotropin-releasing hormone proximal promoter.</strong> Molec. Endocr. 14: 1246-1256, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10935548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10935548</a>] [<a href="https://doi.org/10.1210/mend.14.8.0509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10935548">Kelley et al. (2000)</a> identified a highly conserved bicoid-related Otx target sequence within the proximal promoter region of the Gnrh gene from several species. This element from the rat Gnrh promoter binds baculovirus-expressed Otx2 protein and Otx2 protein in nuclear extracts of a hypothalamic Gnrh-expressing mouse neuronal cell line, GT1-7. Transient transfection assays indicated that the Gnrh promoter Otx/bicoid site is required for specific expression of the Gnrh gene in GT1-7 cells. Thus, the Gnrh proximal promoter is regulated by the Otx2 homeoprotein. The authors concluded that Otx2 is important in the development of the Gnrh neuron and/or in the maintenance of Gnrh expression in the adult mouse hypothalamus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10935548" 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>Olfactory neurons and GNRH neurons share a common origin during development. In the nasal epithelia, GNRH neurons persist throughout fetal life and adulthood. <a href="#3" class="mim-tip-reference" title="Barni, T., Maggi, M., Fantoni, G., Granchi, S., Mancina, R., Gulisano, M., Marra, F., Macorsini, E., Luconi, M., Rotella, C., Serio, M., Balboni, G. C., Vannelli, G. B. <strong>Sex steroids and odorants modulate gonadotropin-releasing hormone secretion in primary cultures of human olfactory cells.</strong> J. Clin. Endocr. Metab. 84: 4266-4273, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10566683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10566683</a>] [<a href="https://doi.org/10.1210/jcem.84.11.6150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10566683">Barni et al. (1999)</a> reported that human olfactory cells express the GNRH1 gene and protein. The release of GNRH was time-dependent and was positively affected by sex steroids and odorants. The authors stated that this was the first time that primary cell cultures from human fetal olfactory neuroepithelium have been shown to express and release GNRH. They suggested that these cultures, which are sensitive to sex steroids and odorants, could be useful models in the study of the complex array of regulatory factors that finely tune GNRH secretion in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10566683" 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>Gametes and preimplantation embryos express GNRH and GNRH receptor (GNRHR; <a href="/entry/138850">138850</a>) at both mRNA and protein levels. <a href="#5" class="mim-tip-reference" title="Casan, E. M., Raga, F., Bonilla-Musoles, F., Polan, M. L. <strong>Human oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and implantation.</strong> J. Clin. Endocr. Metab. 85: 1377-1381, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10770169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10770169</a>] [<a href="https://doi.org/10.1210/jcem.85.4.6503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10770169">Casan et al. (2000)</a> used RT-PCR and immunohistochemical techniques to investigate GNRH mRNA and protein expression in human fallopian tubes throughout the menstrual cycle of premenopausal fertile patients. Their results revealed cycle-dependent production of an oviductal GnRH with expression during the luteal phase. Moreover, GnRH immunostaining was localized in the tubal epithelium during the luteal phase. They concluded that during reproductive life, oviductal GNRH may play a substantial paracrine/autocrine role in human fertilization, early embryonic development, and implantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10770169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chen, A., Ganor, Y., Rahimipour, S., Ben-Aroya, N., Koch, Y., Levite, M. <strong>The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs.</strong> Nature Med. 8: 1421-1426, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447356</a>] [<a href="https://doi.org/10.1038/nm1202-801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447356">Chen et al. (2002)</a> found that human normal and leukemic T cells produce GNRH2 (<a href="/entry/602352">602352</a>) and GNRH1. Exposure of normal or cancerous human or mouse T cells to GNRH2 or GNRH1 triggered de novo gene transcription and cell-surface expression of the laminin receptor (<a href="/entry/150370">150370</a>), which is involved in cellular adhesion and migration and in tumor invasion and metastasis. GNRH2 or GNRH1 also induced adhesion to laminin and chemotaxis toward SDF1A (<a href="/entry/600835">600835</a>), and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GNRH1. A specific GNRH1 receptor antagonist blocked GNRH1 but not GNRH2-induced effects, which was suggestive of signaling through distinct receptors. <a href="#8" class="mim-tip-reference" title="Chen, A., Ganor, Y., Rahimipour, S., Ben-Aroya, N., Koch, Y., Levite, M. <strong>The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs.</strong> Nature Med. 8: 1421-1426, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447356</a>] [<a href="https://doi.org/10.1038/nm1202-801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447356">Chen et al. (2002)</a> suggested that GNRH2 and GNRH1, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis, and homing to specific organs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether genetic variation within either the GNRHR (<a href="/entry/138850">138850</a>) or GNRH1 genes contributes to the regulation of pubertal timing in the general population, <a href="#21" class="mim-tip-reference" title="Sedlmeyer, I. L., Pearce, C. L., Trueman, J. A., Butler, J. L., Bersaglieri, T., Read, A. P., Clayton, P. E., Kolonel, L. N., Henderson, B. E., Hirschhorn, J. N., Palmert, M. R. <strong>Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing.</strong> J. Clin. Endocr. Metab. 90: 1091-1099, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15546906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15546906</a>] [<a href="https://doi.org/10.1210/jc.2004-0649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15546906">Sedlmeyer et al. (2005)</a> performed sequence analysis and haplotype-based association studies in individuals with later than average pubertal development. All observed associations were relatively modest and only nominally statistically significant. The authors concluded that genetic variation in GHRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15546906" 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="Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., Cai, D. <strong>Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH.</strong> Nature 497: 211-216, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23636330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23636330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23636330[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/nature12143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23636330">Zhang et al. (2013)</a> showed that the hypothalamus is important for the development of whole-body aging in mice, and that the underlying basis involves hypothalamic immunity mediated by I-kappa-B kinase-beta (IKK-beta; <a href="/entry/603258">603258</a>), NF-kappa-B (<a href="/entry/164011">164011</a>), and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and life span extension were achieved in mice by preventing aging-related hypothalamic or brain IKK-beta and NF-kappa-B activation. Mechanistic studies further revealed that IKK-beta and NF-kappa B inhibit GNRH to mediate aging-related hypothalamic GNRH decline, and GNRH treatment amends aging-impaired neurogenesis and decelerates aging. <a href="#26" class="mim-tip-reference" title="Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., Cai, D. <strong>Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH.</strong> Nature 497: 211-216, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23636330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23636330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23636330[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/nature12143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23636330">Zhang et al. (2013)</a> concluded that the hypothalamus plays a programmatic role in aging development via immune-neuroendocrine integration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23636330" 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="Yang-Feng, T. L., Seeburg, P. H., Francke, U. <strong>Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2-p21).</strong> Somat. Cell Molec. Genet. 12: 95-100, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3511544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3511544</a>] [<a href="https://doi.org/10.1007/BF01560732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3511544">Yang-Feng et al. (1986)</a> used a cDNA clone from human placenta to assign the LHRH gene to 8p21-p11.2 by in situ hybridization and corroborated the assignment to chromosome 8 by Southern blot analysis of somatic hybrid cell DNAs. <a href="#23" class="mim-tip-reference" title="Williamson, P., Lang, J., Boyd, Y. <strong>The gonadotropin-releasing hormone (Gnrh) gene maps to mouse chromosome 14 and identifies a homologous region on human chromosome 8.</strong> Somat. Cell Molec. Genet. 17: 609-615, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1767338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1767338</a>] [<a href="https://doi.org/10.1007/BF01233626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1767338">Williamson et al. (1991)</a> mapped the Gnrh gene in the mouse to chromosome 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3511544+1767338" 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>In a Romanian brother and sister from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism (HH12; <a href="/entry/614841">614841</a>), <a href="#4" class="mim-tip-reference" title="Bouligand, J., Ghervan, C., Tello, J. A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R. P., Guiochon-Mantel, A., Young, J. <strong>Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.</strong> New Eng. J. Med. 360: 2742-2748, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19535795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19535795</a>] [<a href="https://doi.org/10.1056/NEJMoa0900136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19535795">Bouligand et al. (2009)</a> identified homozygosity for a 1-bp insertion in the GNRH1 gene (<a href="#0001">152760.0001</a>). GnRH was undetectable in medium conditioned by AtT20 pituitary cells transfected with mutant GNRH1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19535795" 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="#7" class="mim-tip-reference" title="Chan, Y.-M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., Jr., Amory, J. K., Pitteloud, N., Seminara, S. B. <strong>GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 106: 11703-11708, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19567835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19567835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19567835[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.0903449106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19567835">Chan et al. (2009)</a> identified homozygosity for a 1-bp deletion in an Armenian boy with hypogonadotropic hypogonadism (<a href="#0002">152760.0002</a>). The mutation status of his parents was not reported, but the deletion was not found in 192 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19567835" 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>Oligogenic Inheritance</em></strong></p><p>
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In a cohort of 310 patients with normosmic HH, <a href="#7" class="mim-tip-reference" title="Chan, Y.-M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., Jr., Amory, J. K., Pitteloud, N., Seminara, S. B. <strong>GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 106: 11703-11708, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19567835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19567835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19567835[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.0903449106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19567835">Chan et al. (2009)</a> analyzed the HH-associated genes GNRH1, FGFR1 (<a href="/entry/136350">136350</a>), and PROKR2 (<a href="/entry/607123">607123</a>), and identified rare heterozygous variants in all 3 genes in the proband of a 3-generation pedigree: R31C in GNRH1, I239T in FGFR1, and S202G in PROKR2. The proband had affected twin daughters, one of whom carried the GNRH1 and FGFR1 variants, whereas the other twin and an affected niece carried only the GNRH1 variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19567835" 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>In the rat, <a href="#1" class="mim-tip-reference" title="Adelman, J. P., Bond, C. T., Douglass, J., Herbert, E. <strong>Two mammalian genes transcribed from opposite strands of the same DNA locus.</strong> Science 235: 1514-1517, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3547652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3547652</a>] [<a href="https://doi.org/10.1126/science.3547652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3547652">Adelman et al. (1987)</a> found that whereas GNRH is encoded by 1 DNA strand, another DNA strand is transcribed into RNA of unknown function. The second gene, called SH, produces transcripts found in the heart, whereas GNRH is expressed in the central nervous system. The RNA transcribed from each of the 2 DNA strands is spliced and polyadenylated, and share significant exon domains. (The Gart locus of Drosophila, known to encode 3 purine pathway enzymatic activities (see <a href="/entry/138440">138440</a>), contains an entire gene encoding a cuticle protein, 'nested,' within the first Gart intron and transcribed from the opposite DNA strand.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3547652" 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="#18" class="mim-tip-reference" title="Mason, A. J., Hayflick, J. S., Zoeller, R. T., Young, W. S., III, Phillips, H. S., Nikolics, K., Seeburg, P. H. <strong>A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the 'hpg' mouse.</strong> Science 234: 1366-1371, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3024317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3024317</a>] [<a href="https://doi.org/10.1126/science.3024317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3024317">Mason et al. (1986)</a> demonstrated that hypogonadism in the hpg (hypogonadal) mouse is caused by a deletional mutation of at least 33.5 kb encompassing the distal half of the gene for the common biosynthetic precursor of gonadotropin-releasing hormone and GNRH-associated peptide (GAP). The partially deleted gene was found to be transcriptionally active as revealed by in situ hybridization histochemistry of hpg hypothalamic tissue sections, but immunocytochemical analysis failed to show the presence of antigen corresponding to any part of the precursor protein. GAP is the same as PIF; it possesses potent prolactin release inhibitory activity (<a href="#20" class="mim-tip-reference" title="Nikolics, K., Mason, A. J., Szonyi, E., Ramachandran, J., Seeburg, P. H. <strong>A prolactin-inhibiting factor within the precursor for human gonadotropin-releasing hormone.</strong> Nature 316: 511-517, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2863757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2863757</a>] [<a href="https://doi.org/10.1038/316511a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2863757">Nikolics et al., 1985</a>). Interestingly, the part of the gene coding for the GNRH decapeptide is left intact. The lack of GNRH in the hpg mouse remains unexplained. <a href="#19" class="mim-tip-reference" title="Mason, A. J., Pitts, S. L., Nikolics, K., Szonyi, E., Wilcox, J. N., Seeburg, P. H., Stewart, T. A. <strong>The hypogonadal mouse: reproductive functions restored by gene therapy.</strong> Science 234: 1372-1378, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3097822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3097822</a>] [<a href="https://doi.org/10.1126/science.3097822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3097822">Mason et al. (1986)</a> found that introduction of an intact GNRH gene into the genome of the hpg mouse resulted in complete reversal of the hypogonadal phenotype. Transgenic hpg/hpg homozygotes of both sexes were capable of mating and producing offspring. <a href="#6" class="mim-tip-reference" title="Cattanach, B. M., Iddon, C. A., Charlton, H. M., Chiappa, S. A., Fink, G. <strong>Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism.</strong> Nature 269: 338-340, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/198666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">198666</a>] [<a href="https://doi.org/10.1038/269338a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="198666">Cattanach et al. (1977)</a> gave the original description of the hpg mouse. They suggested that the hpg mouse might be analogous to the human disorder described by <a href="#13" class="mim-tip-reference" title="Ewer, R. W. <strong>Familial monotropic pituitary gonadotropin insufficiency.</strong> J. Clin. Endocr. 28: 783-788, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5656436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5656436</a>] [<a href="https://doi.org/10.1210/jcem-28-6-783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5656436">Ewer (1968)</a> as familial monotropic pituitary insufficiency transmitted as an autosomal recessive; see <a href="/entry/614841">614841</a>. <a href="#14" class="mim-tip-reference" title="Gibson, M. J., Krieger, D. T., Charlton, H. M., Zimmerman, E. A., Silverman, A.-J., Perlow, M. J. <strong>Mating and pregnancy can occur in genetically hypogonadal mice with preoptic area brain grafts.</strong> Science 225: 949-951, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6382608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6382608</a>] [<a href="https://doi.org/10.1126/science.6382608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6382608">Gibson et al. (1984)</a> demonstrated that preoptic area brain grafts restored the capacity for mating and pregnancy in the hpg female mouse described by <a href="#6" class="mim-tip-reference" title="Cattanach, B. M., Iddon, C. A., Charlton, H. M., Chiappa, S. A., Fink, G. <strong>Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism.</strong> Nature 269: 338-340, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/198666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">198666</a>] [<a href="https://doi.org/10.1038/269338a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="198666">Cattanach et al. (1977)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=198666+2863757+6382608+5656436+3097822+3024317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>2 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=152760[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 12 WITHOUT ANOSMIA (1 family)</strong>
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GNRH1, 1-BP INS, 18A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777758 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777758;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=rs587777758" 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=rs587777758" 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=RCV000030900" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030900" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030900</a>
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<p>In a Romanian brother and sister from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism (HH12; <a href="/entry/614841">614841</a>), <a href="#4" class="mim-tip-reference" title="Bouligand, J., Ghervan, C., Tello, J. A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R. P., Guiochon-Mantel, A., Young, J. <strong>Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.</strong> New Eng. J. Med. 360: 2742-2748, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19535795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19535795</a>] [<a href="https://doi.org/10.1056/NEJMoa0900136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19535795">Bouligand et al. (2009)</a> identified homozygosity for a 1-bp insertion (18insA) in the GNRH1 gene, predicted to result in an aberrant peptide with a truncated peptide-signal sequence devoid of its hydrophobic core and a total length of 42 amino acids instead of the normal 92. The unaffected parents and an unaffected sister were heterozygous for the mutation, as was 1 of 200 ancestrally matched Romanian controls; haplotype analysis suggested a founding event 8 to 50 generations earlier. The mutation was not found in 100 unrelated Caucasian eugonadal individuals or in 145 unrelated Caucasian patients with sporadic normosmic IHH. Transfection studies using AtT20 pituitary cells showed that GnRH was present in medium conditioned by cells transfected with wildtype GNRH1, but was undetectable in medium conditioned by cells transfected with the GNRH1 18insA mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19535795" 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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GNRH1, 1-BP DEL, 87A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777859 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777859;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=rs587777859" 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=rs587777859" 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=RCV000144705" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144705" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144705</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to hypogonadotropic hypogonadism (see <a href="/entry/614841">614841</a>) has not been confirmed.</p><p><a href="#7" class="mim-tip-reference" title="Chan, Y.-M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., Jr., Amory, J. K., Pitteloud, N., Seminara, S. B. <strong>GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 106: 11703-11708, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19567835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19567835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19567835[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.0903449106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19567835">Chan et al. (2009)</a> analyzed the GNRH1 gene in 310 patients with normosmic hypogonadotropic hypogonadism (HH), and identified homozygosity for a 1-bp deletion (c.87delA) in an Armenian boy. The mutation causes a frameshift predicted to result in a premature termination codon (Gly29GlyfsTer12). The mutation status of his unaffected parents, who came from the same small village in Armenia, was not reported; however, the deletion was not found in 192 controls. The authors also sequenced the FGFR1 (<a href="/entry/136350">136350</a>) and PROKR2 (<a href="/entry/607123">607123</a>) genes in the proband but detected no mutations. The affected boy, who was initially evaluated at 8.75 years of age for micropenis and cryptorchidism, had no skeletal or midline defects. Luteinizing hormone (LH; <a href="/entry/152780">152780</a>) and follicle-stimulating hormone (FSH; see <a href="/entry/136530">136530</a>) levels were less than 0.5 IU/L; anti-mullerian hormone (AMH; <a href="/entry/600957">600957</a>) was low normal, indicating the presence of testicular Sertoli cells. A human chorionic gonadotropin (hCG; see <a href="/entry/118860">118860</a>) stimulation test produced no change in serum testosterone. Testicular biopsies at the time of orchiopexy showed immature seminiferous tubules with no lumen, gonocyte-like cells, immature Sertoli cells, and interstitial fibrosis with spindle-shaped myofibroblasts. At 13.5 years of age, he underwent a GnRH stimulation test due to lack of pubertal development, with minimal increases in LH and FSH. He had a normal sense of smell on formal testing. Testosterone treatment resulted in linear growth and development of secondary sexual characteristics, which at 15.5 years of age included facial hair and Tanner stage V pubic hair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19567835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Adelman1987" class="mim-anchor"></a>
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Adelman, J. P., Bond, C. T., Douglass, J., Herbert, E.
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<strong>Two mammalian genes transcribed from opposite strands of the same DNA locus.</strong>
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Science 235: 1514-1517, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3547652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3547652</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3547652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.3547652" target="_blank">Full Text</a>]
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Adelman, J. P., Mason, A. J., Hayflick, J. S., Seeburg, P. H.
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<strong>Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat.</strong>
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Proc. Nat. Acad. Sci. 83: 179-183, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2867548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2867548</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2867548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.83.1.179" target="_blank">Full Text</a>]
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Barni, T., Maggi, M., Fantoni, G., Granchi, S., Mancina, R., Gulisano, M., Marra, F., Macorsini, E., Luconi, M., Rotella, C., Serio, M., Balboni, G. C., Vannelli, G. B.
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<strong>Sex steroids and odorants modulate gonadotropin-releasing hormone secretion in primary cultures of human olfactory cells.</strong>
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J. Clin. Endocr. Metab. 84: 4266-4273, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10566683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10566683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10566683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.84.11.6150" target="_blank">Full Text</a>]
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Bouligand, J., Ghervan, C., Tello, J. A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R. P., Guiochon-Mantel, A., Young, J.
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<strong>Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.</strong>
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New Eng. J. Med. 360: 2742-2748, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19535795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19535795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19535795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa0900136" target="_blank">Full Text</a>]
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Casan, E. M., Raga, F., Bonilla-Musoles, F., Polan, M. L.
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<strong>Human oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and implantation.</strong>
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J. Clin. Endocr. Metab. 85: 1377-1381, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10770169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10770169</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10770169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.85.4.6503" target="_blank">Full Text</a>]
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<a id="Cattanach1977" class="mim-anchor"></a>
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Cattanach, B. M., Iddon, C. A., Charlton, H. M., Chiappa, S. A., Fink, G.
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<strong>Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism.</strong>
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Nature 269: 338-340, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/198666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">198666</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=198666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/269338a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm1202-801" target="_blank">Full Text</a>]
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Wolfe2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wolfe, A., Kim, H. H., Tobet, S., Stafford, D. E. J., Radovick, S.
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<strong>Identification of a discrete promoter region of the human GnRH gene that is sufficient for directing neuron-specific expression: a role for POU homeodomain transcription factors.</strong>
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Molec. Endocr. 16: 435-449, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/mend.16.3.0780" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Yang-Feng1986" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang-Feng, T. L., Seeburg, P. H., Francke, U.
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<strong>Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2-p21).</strong>
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Somat. Cell Molec. Genet. 12: 95-100, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3511544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3511544</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3511544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01560732" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Zhang2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., Cai, D.
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<strong>Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH.</strong>
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Nature 497: 211-216, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23636330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23636330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23636330[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23636330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature12143" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 10/23/2014
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 5/22/2013<br>Marla J. F. O'Neill - updated : 9/27/2012<br>Marla J. F. O'Neill - updated : 7/14/2009<br>John A. Phillips, III - updated : 8/22/2006<br>John A. Phillips, III - updated : 1/29/2004<br>Victor A. McKusick - updated : 3/14/2003<br>Ada Hamosh - updated : 2/13/2003<br>John A. Phillips, III - updated : 10/10/2002<br>John A. Phillips, III - updated : 7/12/2002<br>John A. Phillips, III - updated : 7/9/2002<br>John A. Phillips, III - updated : 8/17/2001<br>John A. Phillips, III - updated : 11/10/2000<br>John A. Phillips, III - updated : 11/10/2000<br>John A. Phillips, III - updated : 4/13/1999<br>John A. Phillips, III - updated : 12/20/1996<br>Victor A. McKusick - updated : 3/4/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/17/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/21/2020<br>carol : 04/13/2016<br>carol : 10/23/2014<br>mcolton : 10/23/2014<br>carol : 10/15/2014<br>mcolton : 10/14/2014<br>mcolton : 10/10/2014<br>alopez : 10/10/2014<br>alopez : 5/22/2013<br>carol : 9/27/2012<br>terry : 3/10/2011<br>alopez : 3/9/2011<br>terry : 9/8/2010<br>carol : 7/14/2009<br>terry : 7/14/2009<br>carol : 3/14/2007<br>carol : 3/14/2007<br>alopez : 8/22/2006<br>alopez : 1/29/2004<br>alopez : 1/29/2004<br>tkritzer : 11/6/2003<br>tkritzer : 11/5/2003<br>tkritzer : 11/5/2003<br>carol : 9/12/2003<br>carol : 3/21/2003<br>carol : 3/21/2003<br>tkritzer : 3/18/2003<br>terry : 3/14/2003<br>alopez : 2/19/2003<br>terry : 2/13/2003<br>alopez : 10/10/2002<br>alopez : 7/12/2002<br>alopez : 7/9/2002<br>alopez : 10/18/2001<br>cwells : 8/22/2001<br>cwells : 8/17/2001<br>alopez : 3/23/2001<br>terry : 11/10/2000<br>terry : 11/10/2000<br>mgross : 4/16/1999<br>mgross : 4/13/1999<br>mark : 2/12/1998<br>terry : 2/10/1998<br>alopez : 7/28/1997<br>alopez : 7/10/1997<br>terry : 7/8/1997<br>jenny : 5/21/1997<br>jenny : 5/21/1997<br>terry : 3/5/1997<br>mark : 3/4/1997<br>terry : 3/3/1997<br>mimadm : 11/6/1994<br>terry : 5/11/1994<br>supermim : 3/19/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 152760
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GONADOTROPIN-RELEASING HORMONE 1; GNRH1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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GNRH<br />
|
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LUTEINIZING HORMONE-RELEASING HORMONE; LHRH
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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PROLACTIN RELEASE-INHIBITING FACTOR, INCLUDED; PIF, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GNRH1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 8p21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:25,419,258-25,425,040 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
|
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<tr class="active">
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<th>
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Location
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</th>
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<th>
|
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
8p21.2
|
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</span>
|
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</td>
|
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|
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<td>
|
|
<span class="mim-font">
|
|
?Hypogonadotropic hypogonadism 12 with or without anosmia
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
614841
|
|
</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Luteinizing hormone-releasing hormone (LHRH), a decapeptide, is a key molecule in the hypothalamic-pituitary-gonadal axis that controls human reproduction. It is produced by hypothalamic neurons, secreted in a pulsatile manner into the capillary plexus of the median eminence, and effects the release of luteinizing hormone and follicle-stimulating hormone from gonadotropic cells of the anterior pituitary. Seeburg and Adelman (1984) isolated cloned genomic and cDNA encoding the precursor of LHRH. These DNA sequences code for a protein of 92 amino acids in which the LHRH decapeptide is preceded by a signal peptide of 23 amino acids and followed by a gly-lys-arg sequence as expected for enzymatic cleavage of the decapeptide from its precursor and amidation of the C terminus of LHRH. LHRH, also referred to as 'gonadotropin-releasing hormone' (GNRH), and prolactin release-inhibiting factor (PIF) are derived from the same 92-amino acid precursor protein, which is encoded by a single gene. (PIF has also been used as the symbol for a parotid salivary protein; see 168730.) </p><p>Hayflick et al. (1989) reported the complete nucleotide sequence of the GNRH gene. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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|
<p>Adelman et al. (1986) determined that the GNRH genes of man and rat have a similar arrangement of 4 exons. </p><p>The GNRH1 gene is exclusively expressed in a discrete population of neurons in the hypothalamus. To explore the protein-DNA interactions that occur within the GNRH1 promoter and the role of these interactions in targeting GNRH1 gene expression, Eraly et al. (1998) mutagenized individual binding sites in the proximal promoter of the GNRH1 gene. DNAase I protection experiments revealed that footprint-2, a 51-bp sequence that confers a 20-fold induction of the GNRH1 gene, is composed of at least 3 independent protein-binding sites. Mutations in footprint-4 also decreased GNRH1 gene expression. Mobility shift cross-competition and antibody shift experiments demonstrated that OCT1 (602607) binds the octamer motifs within footprints-2 and -4. Eraly et al. (1998) concluded that OCT1 plays a critical role in the regulation of GNRH1 transcription, binding functional elements in both the distal enhancer and the proximal promoter conserved region. </p><p>Wolfe et al. (2002) used a transgenic mouse model to isolate cis-regulatory elements important for directing gene expression to Gnrh neurons in the hypothalamus. Cell-specific expression, with the criterion being luciferase expression directed to Gnrh neurons of the hypothalamus, was observed when 992 bp, but not 795 bp, of the human GNRH1 gene promoter were used. Tissue-specific expression was also observed when a deletion construct containing the region from -992 to -763 was fused to a minimal 48-bp promoter fragment fused to a luciferase reporter gene. These data indicate that the region between -992 and -795 contains elements both essential and sufficient for targeting gene expression to Gnrh neurons. This promoter region contains 2 DNA binding sites for the POU class of transcription factors, each of which specifically interacted with the POU homeodomain proteins Brn2 (600494) and Oct1. Functional studies demonstrated that Brn2 increased promoter activity of the human and mouse GNRH1 genes. </p>
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</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Neuron-specific expression of the GNRH1 gene is dependent on an upstream multicomponent enhancer. This enhancer is functional in a small population of GNRH1-producing hypothalamic neurons which, through the secretion of GNRH1, mediates central nervous system control of reproductive function. GNRH1 enhancer function requires activation by the GATA family of transcription factors that act through tandem consensus GATA-binding motifs, termed GATA-A and GATA-B. See GATA4 (600576). Lawson et al. (1998) showed that 2 newly identified DNA-binding factors, which they referred to as GBF-A1/A2 and GBF-B1, bind the GNRH1 enhancer at sites overlapping the GATA factor-binding motifs. In vitro bindings of GATA, GBF-A1/A2, and GBF-B1 to the GNRH1 enhancer sequences occurred independently. Utilizing a GNRH1-expressing neuronal cell line as a model system, they showed by transient transfection that GBF-B1 is necessary for enhancer activity and independently activates the GNRH1 promoter. Transactivation of the GNRH1 enhancer in GT1 cells and in NIH 3T3 cells by GATA4 was modulated by GBF-B1 binding, suggesting that GBF-B1 interferes with GATA factor binding through a steric mechanism. </p><p>Dong et al. (1997) localized 4 specific nuclear protein-binding elements in the human GNRH1 upstream promoter. To test whether these 4 elements are reproductive tissue-specific, Dong et al. (2001) placed the 4 elements upstream to a thymidine kinase (188300) promoter/luciferase reporter gene and transfected the constructs into human placental choriocarcinoma (JEG-3) cells. Deletion of element 4 (E4, -987/-968) significantly decreased (4-fold) the luciferase activity. Further deletion of the other elements (E3, -960/-940 or E3 and E2 in combination, -919/-896) only slightly decreased the luciferase activity. In contrast, deletion of element 1 (E1, -876/-851) caused a 2-fold loss of luciferase activity and elimination of E2 and E3 only lost less than 2-fold of the luciferase activity. Furthermore, E4 DNA-protein complex was supershifted by antibodies against octamer-binding transcription factor-1 (OCT1), indicating that OCT1 binds to E4. The authors concluded that all 4 elements are required to confer tissue-specific expression of the GNRH1 gene in JEG-3 cells; however, E4 is the most important for the tissue-specific expression of the GNRH1 gene in JEG-3 cells. OCT1 factor binds with E4 and may be involved in the mediation of the human GNRH1 upstream promoter activity. </p><p>Duan et al. (2002) examined the regulatory elements and signal transduction pathways by which GNRH regulates Egr1 (128990) transcription. Deletion analysis of the murine Egr1 promoter identified 2 regions (-370 to -342 and -116 to -73) that are critical for GNRH responsiveness in alpha-T3 pituitary gonadotrope cells. The first region, which contains 2 serum response elements (SREs), contributed about 70 to 80% of GNRH inducibility, whereas the second region, which contains 2 SREs and 1 Ets binding site, conferred an additional 20 to 30% of activity. Using specific protein kinase inhibitors, GNRH stimulation of Egr1 expression was found to be dependent on PKC/ERK pathways (see 603607). The authors concluded that GNRH stimulation of Egr1 gene expression requires several distinct SREs/Ets elements and a cAMP response element and is mediated via activation of PKC/ERK signaling pathways. </p><p>The Gnrh gene is expressed exclusively in a highly restricted population of approximately 800 neurons in the mediobasal hypothalamus in the mouse. The Otx2 homeoprotein (600037) colocalizes with Gnrh in embryonic mouse brain. Kelley et al. (2000) identified a highly conserved bicoid-related Otx target sequence within the proximal promoter region of the Gnrh gene from several species. This element from the rat Gnrh promoter binds baculovirus-expressed Otx2 protein and Otx2 protein in nuclear extracts of a hypothalamic Gnrh-expressing mouse neuronal cell line, GT1-7. Transient transfection assays indicated that the Gnrh promoter Otx/bicoid site is required for specific expression of the Gnrh gene in GT1-7 cells. Thus, the Gnrh proximal promoter is regulated by the Otx2 homeoprotein. The authors concluded that Otx2 is important in the development of the Gnrh neuron and/or in the maintenance of Gnrh expression in the adult mouse hypothalamus. </p><p>Olfactory neurons and GNRH neurons share a common origin during development. In the nasal epithelia, GNRH neurons persist throughout fetal life and adulthood. Barni et al. (1999) reported that human olfactory cells express the GNRH1 gene and protein. The release of GNRH was time-dependent and was positively affected by sex steroids and odorants. The authors stated that this was the first time that primary cell cultures from human fetal olfactory neuroepithelium have been shown to express and release GNRH. They suggested that these cultures, which are sensitive to sex steroids and odorants, could be useful models in the study of the complex array of regulatory factors that finely tune GNRH secretion in humans. </p><p>Gametes and preimplantation embryos express GNRH and GNRH receptor (GNRHR; 138850) at both mRNA and protein levels. Casan et al. (2000) used RT-PCR and immunohistochemical techniques to investigate GNRH mRNA and protein expression in human fallopian tubes throughout the menstrual cycle of premenopausal fertile patients. Their results revealed cycle-dependent production of an oviductal GnRH with expression during the luteal phase. Moreover, GnRH immunostaining was localized in the tubal epithelium during the luteal phase. They concluded that during reproductive life, oviductal GNRH may play a substantial paracrine/autocrine role in human fertilization, early embryonic development, and implantation. </p><p>Chen et al. (2002) found that human normal and leukemic T cells produce GNRH2 (602352) and GNRH1. Exposure of normal or cancerous human or mouse T cells to GNRH2 or GNRH1 triggered de novo gene transcription and cell-surface expression of the laminin receptor (150370), which is involved in cellular adhesion and migration and in tumor invasion and metastasis. GNRH2 or GNRH1 also induced adhesion to laminin and chemotaxis toward SDF1A (600835), and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GNRH1. A specific GNRH1 receptor antagonist blocked GNRH1 but not GNRH2-induced effects, which was suggestive of signaling through distinct receptors. Chen et al. (2002) suggested that GNRH2 and GNRH1, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis, and homing to specific organs. </p><p>To determine whether genetic variation within either the GNRHR (138850) or GNRH1 genes contributes to the regulation of pubertal timing in the general population, Sedlmeyer et al. (2005) performed sequence analysis and haplotype-based association studies in individuals with later than average pubertal development. All observed associations were relatively modest and only nominally statistically significant. The authors concluded that genetic variation in GHRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population. </p><p>Zhang et al. (2013) showed that the hypothalamus is important for the development of whole-body aging in mice, and that the underlying basis involves hypothalamic immunity mediated by I-kappa-B kinase-beta (IKK-beta; 603258), NF-kappa-B (164011), and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and life span extension were achieved in mice by preventing aging-related hypothalamic or brain IKK-beta and NF-kappa-B activation. Mechanistic studies further revealed that IKK-beta and NF-kappa B inhibit GNRH to mediate aging-related hypothalamic GNRH decline, and GNRH treatment amends aging-impaired neurogenesis and decelerates aging. Zhang et al. (2013) concluded that the hypothalamus plays a programmatic role in aging development via immune-neuroendocrine integration. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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<span class="mim-text-font">
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<p>Yang-Feng et al. (1986) used a cDNA clone from human placenta to assign the LHRH gene to 8p21-p11.2 by in situ hybridization and corroborated the assignment to chromosome 8 by Southern blot analysis of somatic hybrid cell DNAs. Williamson et al. (1991) mapped the Gnrh gene in the mouse to chromosome 14. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In a Romanian brother and sister from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism (HH12; 614841), Bouligand et al. (2009) identified homozygosity for a 1-bp insertion in the GNRH1 gene (152760.0001). GnRH was undetectable in medium conditioned by AtT20 pituitary cells transfected with mutant GNRH1. </p><p>Chan et al. (2009) identified homozygosity for a 1-bp deletion in an Armenian boy with hypogonadotropic hypogonadism (152760.0002). The mutation status of his parents was not reported, but the deletion was not found in 192 controls. </p><p><strong><em>Oligogenic Inheritance</em></strong></p><p>
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In a cohort of 310 patients with normosmic HH, Chan et al. (2009) analyzed the HH-associated genes GNRH1, FGFR1 (136350), and PROKR2 (607123), and identified rare heterozygous variants in all 3 genes in the proband of a 3-generation pedigree: R31C in GNRH1, I239T in FGFR1, and S202G in PROKR2. The proband had affected twin daughters, one of whom carried the GNRH1 and FGFR1 variants, whereas the other twin and an affected niece carried only the GNRH1 variant. </p>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In the rat, Adelman et al. (1987) found that whereas GNRH is encoded by 1 DNA strand, another DNA strand is transcribed into RNA of unknown function. The second gene, called SH, produces transcripts found in the heart, whereas GNRH is expressed in the central nervous system. The RNA transcribed from each of the 2 DNA strands is spliced and polyadenylated, and share significant exon domains. (The Gart locus of Drosophila, known to encode 3 purine pathway enzymatic activities (see 138440), contains an entire gene encoding a cuticle protein, 'nested,' within the first Gart intron and transcribed from the opposite DNA strand.) </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<p>Mason et al. (1986) demonstrated that hypogonadism in the hpg (hypogonadal) mouse is caused by a deletional mutation of at least 33.5 kb encompassing the distal half of the gene for the common biosynthetic precursor of gonadotropin-releasing hormone and GNRH-associated peptide (GAP). The partially deleted gene was found to be transcriptionally active as revealed by in situ hybridization histochemistry of hpg hypothalamic tissue sections, but immunocytochemical analysis failed to show the presence of antigen corresponding to any part of the precursor protein. GAP is the same as PIF; it possesses potent prolactin release inhibitory activity (Nikolics et al., 1985). Interestingly, the part of the gene coding for the GNRH decapeptide is left intact. The lack of GNRH in the hpg mouse remains unexplained. Mason et al. (1986) found that introduction of an intact GNRH gene into the genome of the hpg mouse resulted in complete reversal of the hypogonadal phenotype. Transgenic hpg/hpg homozygotes of both sexes were capable of mating and producing offspring. Cattanach et al. (1977) gave the original description of the hpg mouse. They suggested that the hpg mouse might be analogous to the human disorder described by Ewer (1968) as familial monotropic pituitary insufficiency transmitted as an autosomal recessive; see 614841. Gibson et al. (1984) demonstrated that preoptic area brain grafts restored the capacity for mating and pregnancy in the hpg female mouse described by Cattanach et al. (1977). </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>2 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 12 WITHOUT ANOSMIA (1 family)</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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GNRH1, 1-BP INS, 18A
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<br />
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SNP: rs587777758,
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ClinVar: RCV000030900
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<span class="mim-text-font">
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<p>In a Romanian brother and sister from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism (HH12; 614841), Bouligand et al. (2009) identified homozygosity for a 1-bp insertion (18insA) in the GNRH1 gene, predicted to result in an aberrant peptide with a truncated peptide-signal sequence devoid of its hydrophobic core and a total length of 42 amino acids instead of the normal 92. The unaffected parents and an unaffected sister were heterozygous for the mutation, as was 1 of 200 ancestrally matched Romanian controls; haplotype analysis suggested a founding event 8 to 50 generations earlier. The mutation was not found in 100 unrelated Caucasian eugonadal individuals or in 145 unrelated Caucasian patients with sporadic normosmic IHH. Transfection studies using AtT20 pituitary cells showed that GnRH was present in medium conditioned by cells transfected with wildtype GNRH1, but was undetectable in medium conditioned by cells transfected with the GNRH1 18insA mutant. </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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<h4>
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<span class="mim-font">
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<strong>.0002 VARIANT OF UNKNOWN SIGNIFICANCE</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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GNRH1, 1-BP DEL, 87A
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<br />
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SNP: rs587777859,
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ClinVar: RCV000144705
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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>This variant is classified as a variant of unknown significance because its contribution to hypogonadotropic hypogonadism (see 614841) has not been confirmed.</p><p>Chan et al. (2009) analyzed the GNRH1 gene in 310 patients with normosmic hypogonadotropic hypogonadism (HH), and identified homozygosity for a 1-bp deletion (c.87delA) in an Armenian boy. The mutation causes a frameshift predicted to result in a premature termination codon (Gly29GlyfsTer12). The mutation status of his unaffected parents, who came from the same small village in Armenia, was not reported; however, the deletion was not found in 192 controls. The authors also sequenced the FGFR1 (136350) and PROKR2 (607123) genes in the proband but detected no mutations. The affected boy, who was initially evaluated at 8.75 years of age for micropenis and cryptorchidism, had no skeletal or midline defects. Luteinizing hormone (LH; 152780) and follicle-stimulating hormone (FSH; see 136530) levels were less than 0.5 IU/L; anti-mullerian hormone (AMH; 600957) was low normal, indicating the presence of testicular Sertoli cells. A human chorionic gonadotropin (hCG; see 118860) stimulation test produced no change in serum testosterone. Testicular biopsies at the time of orchiopexy showed immature seminiferous tubules with no lumen, gonocyte-like cells, immature Sertoli cells, and interstitial fibrosis with spindle-shaped myofibroblasts. At 13.5 years of age, he underwent a GnRH stimulation test due to lack of pubertal development, with minimal increases in LH and FSH. He had a normal sense of smell on formal testing. Testosterone treatment resulted in linear growth and development of secondary sexual characteristics, which at 15.5 years of age included facial hair and Tanner stage V pubic hair. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Adelman, J. P., Bond, C. T., Douglass, J., Herbert, E.
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<strong>Two mammalian genes transcribed from opposite strands of the same DNA locus.</strong>
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Science 235: 1514-1517, 1987.
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[PubMed: 3547652]
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[Full Text: https://doi.org/10.1126/science.3547652]
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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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Adelman, J. P., Mason, A. J., Hayflick, J. S., Seeburg, P. H.
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<strong>Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat.</strong>
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Proc. Nat. Acad. Sci. 83: 179-183, 1986.
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[PubMed: 2867548]
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[Full Text: https://doi.org/10.1073/pnas.83.1.179]
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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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Barni, T., Maggi, M., Fantoni, G., Granchi, S., Mancina, R., Gulisano, M., Marra, F., Macorsini, E., Luconi, M., Rotella, C., Serio, M., Balboni, G. C., Vannelli, G. B.
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<strong>Sex steroids and odorants modulate gonadotropin-releasing hormone secretion in primary cultures of human olfactory cells.</strong>
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J. Clin. Endocr. Metab. 84: 4266-4273, 1999.
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[PubMed: 10566683]
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[Full Text: https://doi.org/10.1210/jcem.84.11.6150]
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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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Bouligand, J., Ghervan, C., Tello, J. A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R. P., Guiochon-Mantel, A., Young, J.
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<strong>Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.</strong>
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New Eng. J. Med. 360: 2742-2748, 2009.
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[PubMed: 19535795]
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[Full Text: https://doi.org/10.1056/NEJMoa0900136]
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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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Casan, E. M., Raga, F., Bonilla-Musoles, F., Polan, M. L.
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<strong>Human oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and implantation.</strong>
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J. Clin. Endocr. Metab. 85: 1377-1381, 2000.
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[PubMed: 10770169]
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[Full Text: https://doi.org/10.1210/jcem.85.4.6503]
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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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Cattanach, B. M., Iddon, C. A., Charlton, H. M., Chiappa, S. A., Fink, G.
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<strong>Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism.</strong>
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Nature 269: 338-340, 1977.
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[PubMed: 198666]
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[Full Text: https://doi.org/10.1038/269338a0]
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</p>
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<li>
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<p class="mim-text-font">
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Chan, Y.-M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., Jr., Amory, J. K., Pitteloud, N., Seminara, S. B.
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<strong>GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.</strong>
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Proc. Nat. Acad. Sci. 106: 11703-11708, 2009.
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[PubMed: 19567835]
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[Full Text: https://doi.org/10.1073/pnas.0903449106]
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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., Ganor, Y., Rahimipour, S., Ben-Aroya, N., Koch, Y., Levite, M.
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<strong>The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs.</strong>
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Nature Med. 8: 1421-1426, 2002.
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[PubMed: 12447356]
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[Full Text: https://doi.org/10.1038/nm1202-801]
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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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Dong, K.-W., Yu, K.-L., Chen, Z.-G., Chen, Y.-D., Roberts, J. L.
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<strong>Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene.</strong>
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Endocrinology 138: 2754-2762, 1997.
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[PubMed: 9202214]
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[Full Text: https://doi.org/10.1210/endo.138.7.5249]
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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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Dong, K.-W., Zheng, H.-M., Wen, Z.-Y., Chen, Z.-G.
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<strong>The POU homeodomain protein Oct-1 binds cis-regulatory element essential for the human GnRH upstream promoter activity in the JEG-3 cells.</strong>
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J. Clin. Endocr. Metab. 86: 2838-2844, 2001.
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[PubMed: 11397896]
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[Full Text: https://doi.org/10.1210/jcem.86.6.7548]
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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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Duan, W. R., Ito, M., Park, Y., Maizels, E. T., Hunzicker-Dunn, M., Jameson, J. L.
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<strong>GnRH regulates early growth response protein 1 transcription through multiple promoter elements.</strong>
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Molec. Endocr. 16: 221-233, 2002.
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[PubMed: 11818496]
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[Full Text: https://doi.org/10.1210/mend.16.2.0779]
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</p>
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</li>
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Marla J. F. O'Neill - updated : 10/23/2014<br>Ada Hamosh - updated : 5/22/2013<br>Marla J. F. O'Neill - updated : 9/27/2012<br>Marla J. F. O'Neill - updated : 7/14/2009<br>John A. Phillips, III - updated : 8/22/2006<br>John A. Phillips, III - updated : 1/29/2004<br>Victor A. McKusick - updated : 3/14/2003<br>Ada Hamosh - updated : 2/13/2003<br>John A. Phillips, III - updated : 10/10/2002<br>John A. Phillips, III - updated : 7/12/2002<br>John A. Phillips, III - updated : 7/9/2002<br>John A. Phillips, III - updated : 8/17/2001<br>John A. Phillips, III - updated : 11/10/2000<br>John A. Phillips, III - updated : 11/10/2000<br>John A. Phillips, III - updated : 4/13/1999<br>John A. Phillips, III - updated : 12/20/1996<br>Victor A. McKusick - updated : 3/4/1997
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