3438 lines
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Entry
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- *607123 - PROKINETICIN RECEPTOR 2; PROKR2
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- OMIM
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<p>
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<span class="h4">*607123</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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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607123">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<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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<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 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=ENSG00000101292;t=ENST00000678254" 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=128674" 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=607123" 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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<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=ENSG00000101292;t=ENST00000678254" 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_144773,XM_017027646" 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_144773" 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=607123" 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=08453&isoform_id=08453_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/PROKR2" 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/21327027,21426829,25006243,33112425,85397450,85397998,119630827,147886419,158261013,1034622753,2462579379" 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/Q8NFJ6" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=128674" 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=ENSG00000101292;t=ENST00000678254" 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=PROKR2" 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=PROKR2" 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+128674" 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/PROKR2" 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:128674" 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/128674" 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=chr20&hgg_gene=ENST00000678254.1&hgg_start=5299218&hgg_end=5316954&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:15836" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/prokr2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607123[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607123[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/PROKR2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000101292" 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=PROKR2" 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=PROKR2" 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=PROKR2" 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=PROKR2&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/PA30014" 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:15836" 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:2181363" 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/PROKR2#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:2181363" 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/128674/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=128674" 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://reactome.org/content/query?q=PROKR2&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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607123
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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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PROKINETICIN RECEPTOR 2; PROKR2
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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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PKR2<br />
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G PROTEIN-COUPLED RECEPTOR 73-LIKE 1; GPR73L1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PROKR2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PROKR2</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/20/80?start=-3&limit=10&highlight=80">20p12.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:5299218-5316954&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'})">20:5,299,218-5,316,954</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/20/80?start=-3&limit=10&highlight=80">
|
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20p12.3
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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 3 with or without anosmia
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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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<a href="/entry/244200"> 244200 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<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>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607123" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607123" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<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>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#4" class="mim-tip-reference" title="Lin, D. C.-H., Bullock, C. M., Ehlert, F. J., Chen, J.-L., Tian, H., Zhou, Q.-Y. <strong>Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.</strong> J. Biol. Chem. 277: 19276-19280, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11886876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11886876</a>] [<a href="https://doi.org/10.1074/jbc.M202139200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11886876">Lin et al. (2002)</a> cloned human GPR73L1 (PROKR2) by PCR of a pooled testis and fetal brain cDNA library. They also cloned GPR73 (PROKR1; <a href="/entry/607122">607122</a>), which shares 85% overall sequence identity with GPR73L1. The greatest divergence between the proteins is in the N terminus, and both share about 80% sequence identity with mouse Gpr73. RT-PCR detected expression of GPR73L1 in brain, testis, small intestine, ovary, thyroid, pituitary, and salivary gland. Expression in the small intestine was confined to the ileocecum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11886876" 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="#4" class="mim-tip-reference" title="Lin, D. C.-H., Bullock, C. M., Ehlert, F. J., Chen, J.-L., Tian, H., Zhou, Q.-Y. <strong>Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.</strong> J. Biol. Chem. 277: 19276-19280, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11886876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11886876</a>] [<a href="https://doi.org/10.1074/jbc.M202139200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11886876">Lin et al. (2002)</a> transfected GPR73 and GPR73L1 into Chinese hamster ovary cells and found that both proteins are receptors for prokineticins (see PROK1, <a href="/entry/606233">606233</a>). Both proteins mobilized calcium when exposed to nanomolar concentrations of recombinant PROK1 and PROK2 (<a href="/entry/607002">607002</a>), and the calcium response was insensitive to pertussis toxin, suggesting that the proteins couple exclusively to Gq (<a href="/entry/600998">600998</a>) rather than to Gi/o (see GNAO1, <a href="/entry/139311">139311</a>). PROK1 produced a dose-dependent increase in total inositol phosphate concentrations in transiently transfected COS-7 cells, but neither GPR had an effect on adenylate cyclase (see ADCY3, <a href="/entry/600291">600291</a>). PROK1 induced sustained phosphorylation of p44/p42 MAPK (see MAPK3, <a href="/entry/601795">601795</a>) in cells transfected with GPR73, but not in cells transfected with GPR73L1. PROK2 stimulated MAPK3 phosphorylation in cells transfected with both GPRs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11886876" 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="#4" class="mim-tip-reference" title="Lin, D. C.-H., Bullock, C. M., Ehlert, F. J., Chen, J.-L., Tian, H., Zhou, Q.-Y. <strong>Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.</strong> J. Biol. Chem. 277: 19276-19280, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11886876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11886876</a>] [<a href="https://doi.org/10.1074/jbc.M202139200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11886876">Lin et al. (2002)</a> mapped the PROKR2 gene in silico to chromosome 20p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11886876" 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>Kallmann syndrome (see HH3; <a href="/entry/244200">244200</a>) combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. By use of a candidate gene strategy in a cohort of 192 patients with Kallmann syndrome, <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> identified 10 and 4 different point mutations in the PROKR2 gene and in one of its ligands, PROK2. The mutations in PROKR2 (e.g., <a href="#0001">607123.0001</a>-<a href="#0005">607123.0005</a> and <a href="#0008">607123.0008</a>) were detected in heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation (<a href="#0001">607123.0001</a>) was also heterozygous for a mutation in the KAL1 gene (<a href="/entry/300836#0012">300836.0012</a>), suggesting possible digenic inheritance. The findings of <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> demonstrated that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> noted that some of the mutations identified in the PROK2 and PROKR2 genes were detected in clinically unaffected individuals, indicating that additional genetic or nongenetic factors are involved in disease production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> analyzed the PROKR2 and PROK2 genes and identified 10 and 5 different point mutations, respectively. All 10 mutations in PROKR2 were heterozygous (see, e.g., <a href="#0001">607123.0001</a> and <a href="#0006">607123.0006</a>-<a href="#0009">607123.0009</a>); 1 of the probands (see <a href="#0007">607123.0007</a>) also carried a heterozygous mutation in PROK2 (<a href="/entry/607002#0005">607002.0005</a>). Of the 11 probands with a mutation in PROKR2, 7 had Kallmann syndrome and 4 had normosmic IHH; screening of 5 other HH-associated genes revealed no additional mutations. All mutant alleles appeared to decrease intracellular calcium mobilization; some also exhibited decreased MAPK signaling and decreased receptor expression. <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> concluded that loss-of-function mutations in PROKR2 can cause both Kallmann syndrome and normosmic IHH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By site-directed mutagenesis, <a href="#6" class="mim-tip-reference" title="Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. <strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong> Hum. Molec. Genet. 18: 75-81, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18826963">Monnier et al. (2009)</a> introduced human PROKR2 missense mutations identified in Kallmann syndrome patients into the mouse Prokr2 gene and tested their effects on signaling activity in transfected HEK293 cells by measuring intracellular calcium release upon ligand activation of the receptor. All mutated receptors except one (M323I; <a href="#0005">607123.0005</a>) had decreased signaling activities. The mutations L173R (<a href="#0001">607123.0001</a>), W178S (<a href="#0008">607123.0008</a>), and P290S impaired cell-surface targeting of the receptor. The Q210R mutation (<a href="#0002">607123.0002</a>) abolished ligand binding. Five mutations (R85C, R85H (<a href="#0003">607123.0003</a>), R164Q, R268C, V331M) presumably impaired G protein coupling of the receptor. When wildtype and mutant receptors were coexpressed in HEK293 cells, none of the intracellularly retained mutant receptors affected cell surface-targeting of the wildtype receptor, and none of the mutant receptors properly addressed at the plasma membrane affected wildtype receptor signaling activity. <a href="#6" class="mim-tip-reference" title="Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. <strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong> Hum. Molec. Genet. 18: 75-81, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18826963">Monnier et al. (2009)</a> concluded that their results argued against a dominant-negative effect of the mutations in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18826963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with anosmic hypogonadotropic hypogonadism (HH16; <a href="/entry/614897">614897</a>) who were heterozygous for 2 different missense mutations in the SEMA3A gene (<a href="/entry/603961">603961</a>), <a href="#3" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[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/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> also identified heterozygosity for a missense mutation in PROKR2. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927827" 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="#5" class="mim-tip-reference" title="Matsumoto, S., Yamazaki, C., Masumoto, K., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Takasaki, J., Kamohara, M., Matsuo, A., Ishii, H., Kobori, M., Katoh, M., Matsushime, H., Furuichi, K., Shigeyoshi, Y. <strong>Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2.</strong> Proc. Nat. Acad. Sci. 103: 4140-4145, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537498</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537498[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.0508881103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537498">Matsumoto et al. (2006)</a> found that deletion of the Pkr2 gene in mice led to hypoplasia of the olfactory bulb and reproductive system, including testis, ovary, uterus, vagina, and mammary gland. In Pkr2 -/- mice, plasma levels of testosterone and follicle-stimulating hormone (see FSHB; <a href="/entry/136530">136530</a>) were decreased, and the mRNA levels of gonadotropin-releasing hormone (see GNRH1; <a href="/entry/152760">152760</a>) in the hypothalamus and luteinizing hormone (see LHB; <a href="/entry/152780">152780</a>) and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that GNRH neurons were absent in the hypothalamus in Pkr2 -/- mice. <a href="#5" class="mim-tip-reference" title="Matsumoto, S., Yamazaki, C., Masumoto, K., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Takasaki, J., Kamohara, M., Matsuo, A., Ishii, H., Kobori, M., Katoh, M., Matsushime, H., Furuichi, K., Shigeyoshi, Y. <strong>Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2.</strong> Proc. Nat. Acad. Sci. 103: 4140-4145, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537498</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537498[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.0508881103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537498">Matsumoto et al. (2006)</a> noted that the phenotype was similar to the clinical features of Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16537498" 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="Prosser, H. M., Bradley, A., Chesham, J. E., Ebling, F. J. P., Hastings, M. H., Maywood, E. S. <strong>Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei.</strong> Proc. Nat. Acad. Sci. 104: 648-563, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17202262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17202262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17202262[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.0606884104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17202262">Prosser et al. (2007)</a> found that Prokr2 -/- mice demonstrated partially penetrant postnatal lethality and that surviving mice weighed significantly less than wildtype. Prokr2 -/- mice failed to breed, and they were hypokinetic and lost precision in the timing and onset of nocturnal locomotor activity compared to Prokr +/- mice and wildtype mice. Under both a light/dark cycle and continuous darkness, Prokr -/- mice showed a pronounced temporal redistribution of activity away from early to late circadian night, and they demonstrated disturbed regulation of core body temperature rhythm. In vitro studies of suprachiasmatic nucleus (SCN) slices showed normal circadian oscillation as demonstrated by bioluminescent real-time imaging. <a href="#7" class="mim-tip-reference" title="Prosser, H. M., Bradley, A., Chesham, J. E., Ebling, F. J. P., Hastings, M. H., Maywood, E. S. <strong>Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei.</strong> Proc. Nat. Acad. Sci. 104: 648-563, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17202262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17202262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17202262[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.0606884104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17202262">Prosser et al. (2007)</a> concluded that Prokr2 is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17202262" 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>9 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607123[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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<p><a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> identified a 518T-G transversion in exon 2 of the PROKR2 gene, resulting in a leu173-to-arg (L173R) substitution, in patients with Kallmann syndrome (HH3; <a href="/entry/244200">244200</a>). The mutation was found in heterozygous state in a family and in 3 sporadic cases, in homozygous state in a sporadic case, and in compound heterozygous state with a Q210R mutation (<a href="#0002">607123.0002</a>) in another family. In a sporadic case of Kallmann syndrome, <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> found heterozygosity for L173R as well as heterozygosity for a mutation in the KAL1 gene (<a href="/entry/300836#0012">300836.0012</a>), suggesting digenic inheritance. The L173R and Q210R mutations in the PROKR2 gene were not found in 500 ethnically matched (Caucasian) control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated male patients with Kallmann syndrome, <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> identified heterozygosity for the L173R mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the L173R mutant compared to wildtype in both assays. Both patients had complete absence of puberty with undetectable levels of luteinizing hormone (LH; <a href="/entry/152780">152780</a>), and their sense of smell was below the fifth percentile on olfactory testing; MRI performed in 1 of the patients showed absence of the olfactory bulbs. Additional features included pes planus, pectus excavatum, and synkinesia in 1 patient and cryptorchidism in the other. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. <strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong> Hum. Molec. Genet. 18: 75-81, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18826963">Monnier et al. (2009)</a> performed functional analysis of the L173R mutation in HEK293 cells and demonstrated decreased signaling and impaired cell-surface targeting of the receptor compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18826963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315417 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315417;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315417?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315417" 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=rs74315417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the gln210-to-arg (Q210R) mutation in the PROKR2 gene that was found in compound heterozygous state in patients with Kallmann syndrome (HH3; <a href="/entry/244200">244200</a>) by <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a>, see <a href="#0001">607123.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. <strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong> Hum. Molec. Genet. 18: 75-81, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18826963">Monnier et al. (2009)</a> performed functional analysis of the Q210R mutation in HEK293 cells and demonstrated that the mutation abolished ligand binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18826963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315418 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315418;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315418?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315418" 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=rs74315418" 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=RCV000022408 OR RCV000498536 OR RCV001849252 OR RCV002254257 OR RCV003415639 OR RCV003991566 OR RCV004782005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022408, RCV000498536, RCV001849252, RCV002254257, RCV003415639, RCV003991566, RCV004782005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022408...</a>
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<p>In affected members of a family with Kallmann syndrome (HH3; <a href="/entry/244200">244200</a>), <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> identified heterozygosity for a 254G-A transition in exon 1 of the PROKR2 gene, resulting in an arg85-to-his (R85H) substitution. They identified the same mutation in homozygous state in a sporadic case of Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. <strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong> Hum. Molec. Genet. 18: 75-81, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18826963">Monnier et al. (2009)</a> performed functional analysis of the R85H mutation in HEK293 cells and observed decreased signaling activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18826963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777834 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777834;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777834?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777834" 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=rs587777834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with Kallmann syndrome (HH3; <a href="/entry/244200">244200</a>), <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> identified heterozygosity for a 1-bp deletion (58delC) in exon 1 of the PROKR2 gene, causing a frameshift resulting in a premature termination codon (20fsTer43). In another family with Kallmann syndrome, they found the same mutation in compound heterozygous state with a 969G-A transition resulting in an M323I substitution (<a href="#0005">607123.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" 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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PROKR2, MET323ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315419 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315419;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=rs74315419" 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=rs74315419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the met323-to-ile (M323I) mutation in the PROKR2 gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism-3 with anosmia (HH3; <a href="/entry/244200">244200</a>) by <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a>, see <a href="#0004">607123.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs141090506 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs141090506;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs141090506?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs141090506" 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=rs141090506" 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=RCV000144712 OR RCV000239076 OR RCV000520900 OR RCV002247534 OR RCV003991574 OR RCV004752753" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144712, RCV000239076, RCV000520900, RCV002247534, RCV003991574, RCV004752753" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144712...</a>
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<p>In a female patient with normosmic hypogonadotropic hypogonadism (HH3; <a href="/entry/244200">244200</a>), <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> identified heterozygosity for a c.253C-T transition in the PROKR2 gene, resulting in an arg85-to-cys (R85C) substitution within the first intracellular loop. Functional analysis demonstrated significantly decreased intracellular calcium mobilization with the R85C mutant compared to wildtype. The mutation was not found in 346 control alleles; <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> stated that they detected R85C in 1 of 500 Caucasian control alleles. The patient underwent partial puberty, with primary amenorrhea, but she had Tanner stage IV breast development and exhibited GnRH (<a href="/entry/152760">152760</a>)-induced luteinizing hormone (LH; see <a href="/entry/152780">152780</a>) secretion in the setting of a low-normal estradiol level while still amenorrheic. She had a normal sense of smell on olfactory testing, and MRI showed normal olfactory bulbs. Both of her parents had delayed puberty; their mutation status was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18559922+17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs138672528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138672528;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs138672528?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs138672528" 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=rs138672528" 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=RCV000144713 OR RCV003390830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144713, RCV003390830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144713...</a>
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<p>In a female patient with Kallmann syndrome (HH3; <a href="/entry/244200">244200</a>), <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> identified a heterozygous c.343G-A transition in the PROKR2 gene, resulting in a val115-to-met (V115M) substitution within the first extracellular loop; in addition, a heterozygous mutation in the PROK2 gene (A24P; <a href="/entry/607002#0005">607002.0005</a>) was detected. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the V115M mutant compared to wildtype in both assays. The patient did not undergo puberty, and luteinizing hormone (LH; see <a href="/entry/152780">152780</a>) was undetectable. Olfactory bulbs were absent on MRI. Other features included strabismus, hearing loss, short fourth metacarpal, pes planus, learning disability, and sleep disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs201835496 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201835496;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs201835496?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs201835496" 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=rs201835496" 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=RCV000144714 OR RCV000870421" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144714, RCV000870421" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144714...</a>
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<p>In a patient with sporadic Kallmann syndrome (HH3; <a href="/entry/244200">244200</a>), <a href="#2" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> identified heterozygosity for a c.533G-C transversion in exon 2 of the PROKR2 gene, resulting in a trp178-to-ser (W178S) substitution in the T4 domain. The mutation was not found in 500 ethnically matched (Caucasian) alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male patient with normosmic hypogonadotropic hypogonadism, <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> identified heterozygosity for the W178S mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the W178S mutant compared to wildtype in both assays. The patient did not undergo puberty and had a normal sense of smell on olfactory testing. He exhibited a pulsatile pattern of luteinizing hormone (LH; see <a href="/entry/152780">152780</a>) and had elevated LH and follicle-stimulating hormone (FSH; see <a href="/entry/136435">136435</a>) levels in the setting of hypogonadal testosterone levels. <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> noted that the LH secretion pattern was hypergonadotropic, although not in the range of males with primary gonadal failure, suggesting a dual hypothalamic and gonadal defect that involved insufficient GNRH (<a href="/entry/152760">152760</a>) secretion as well as primary gonadal resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. <strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong> Hum. Molec. Genet. 18: 75-81, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18826963">Monnier et al. (2009)</a> performed functional analysis of the W178S mutation in HEK293 cells and observed impaired cell-surface targeting of the receptor with the W178S mutant compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18826963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs376142095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376142095;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs376142095?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs376142095" 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=rs376142095" 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=RCV000144715 OR RCV001140929 OR RCV002514778" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144715, RCV001140929, RCV002514778" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144715...</a>
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<p>In a male patient with normosmic hypogonadotropic hypogonadism (HH3; <a href="/entry/244200">244200</a>) who experienced reversal of his hypogonadism later in life, <a href="#1" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. <strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong> J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al. (2008)</a> identified heterozygosity for a c.743G-A transition in the PROKR2 gene, resulting in an arg248-to-gln (R248Q) substitution within the last intracellular loop. The mutation was present in heterozygosity in the patient's unaffected father, but was not found in 346 control alleles. Functional analysis demonstrated decreased activity on calcium mobilization assay with the R248Q mutant compared to wildtype. The patient underwent partial puberty with some testicular growth (testicular volume, 6-7 ml) evident at the time of diagnosis. At 28 years of age, after discontinuation of testosterone therapy, he achieved fertility and sustained normal serum testosterone levels thereafter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" 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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Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N.
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<strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong>
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J. Clin. Endocr. Metab. 93: 3551-3559, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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=18559922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P.
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<strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong>
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PLoS Genet. 2: e175, 2006. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" 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/10.1371/journal.pgen.0020175" target="_blank">Full Text</a>]
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Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others.
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<strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong>
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PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[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=22927827" 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/10.1371/journal.pgen.1002896" 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="4" class="mim-anchor"></a>
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<a id="Lin2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lin, D. C.-H., Bullock, C. M., Ehlert, F. J., Chen, J.-L., Tian, H., Zhou, Q.-Y.
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|
<strong>Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.</strong>
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J. Biol. Chem. 277: 19276-19280, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11886876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11886876</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11886876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M202139200" 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="5" class="mim-anchor"></a>
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<a id="Matsumoto2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Matsumoto, S., Yamazaki, C., Masumoto, K., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Takasaki, J., Kamohara, M., Matsuo, A., Ishii, H., Kobori, M., Katoh, M., Matsushime, H., Furuichi, K., Shigeyoshi, Y.
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<strong>Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2.</strong>
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Proc. Nat. Acad. Sci. 103: 4140-4145, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537498</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537498[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=16537498" 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.0508881103" 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="6" class="mim-anchor"></a>
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<a id="Monnier2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P.
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|
<strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong>
|
|
Hum. Molec. Genet. 18: 75-81, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18826963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18826963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18826963[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=18826963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn318" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Prosser2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Prosser, H. M., Bradley, A., Chesham, J. E., Ebling, F. J. P., Hastings, M. H., Maywood, E. S.
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|
<strong>Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 648-563, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17202262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17202262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17202262[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=17202262" 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.0606884104" 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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<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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Marla J. F. O'Neill - updated : 10/28/2013<br>Marla J. F. O'Neill - updated : 9/27/2012<br>George E. Tiller - updated : 10/23/2009<br>Cassandra L. Kniffin - updated : 6/15/2007<br>Victor A. McKusick - updated : 11/21/2006<br>Patricia A. Hartz - updated : 5/3/2006
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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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Patricia A. Hartz : 7/30/2002
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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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|
carol : 06/29/2015
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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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mcolton : 6/16/2015<br>carol : 10/24/2014<br>mcolton : 10/23/2014<br>carol : 10/28/2013<br>carol : 9/27/2012<br>alopez : 3/10/2011<br>wwang : 11/3/2009<br>terry : 10/23/2009<br>wwang : 6/29/2007<br>ckniffin : 6/15/2007<br>carol : 12/5/2006<br>terry : 11/21/2006<br>wwang : 5/8/2006<br>terry : 5/3/2006<br>carol : 7/30/2002
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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> 607123
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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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|
|
PROKINETICIN RECEPTOR 2; PROKR2
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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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PKR2<br />
|
|
G PROTEIN-COUPLED RECEPTOR 73-LIKE 1; GPR73L1
|
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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-text-font">
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<strong><em>HGNC Approved Gene Symbol: PROKR2</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: 20p12.3
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|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 20:5,299,218-5,316,954 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<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>
|
|
<td rowspan="1">
|
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<span class="mim-font">
|
|
20p12.3
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Hypogonadotropic hypogonadism 3 with or without anosmia
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
244200
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</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">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</h4>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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|
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|
<span class="mim-text-font">
|
|
<p>Lin et al. (2002) cloned human GPR73L1 (PROKR2) by PCR of a pooled testis and fetal brain cDNA library. They also cloned GPR73 (PROKR1; 607122), which shares 85% overall sequence identity with GPR73L1. The greatest divergence between the proteins is in the N terminus, and both share about 80% sequence identity with mouse Gpr73. RT-PCR detected expression of GPR73L1 in brain, testis, small intestine, ovary, thyroid, pituitary, and salivary gland. Expression in the small intestine was confined to the ileocecum. </p>
|
|
</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>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
|
<p>Lin et al. (2002) transfected GPR73 and GPR73L1 into Chinese hamster ovary cells and found that both proteins are receptors for prokineticins (see PROK1, 606233). Both proteins mobilized calcium when exposed to nanomolar concentrations of recombinant PROK1 and PROK2 (607002), and the calcium response was insensitive to pertussis toxin, suggesting that the proteins couple exclusively to Gq (600998) rather than to Gi/o (see GNAO1, 139311). PROK1 produced a dose-dependent increase in total inositol phosphate concentrations in transiently transfected COS-7 cells, but neither GPR had an effect on adenylate cyclase (see ADCY3, 600291). PROK1 induced sustained phosphorylation of p44/p42 MAPK (see MAPK3, 601795) in cells transfected with GPR73, but not in cells transfected with GPR73L1. PROK2 stimulated MAPK3 phosphorylation in cells transfected with both GPRs. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
|
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|
<span class="mim-text-font">
|
|
<p>Lin et al. (2002) mapped the PROKR2 gene in silico to chromosome 20p13. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Kallmann syndrome (see HH3; 244200) combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. By use of a candidate gene strategy in a cohort of 192 patients with Kallmann syndrome, Dode et al. (2006) identified 10 and 4 different point mutations in the PROKR2 gene and in one of its ligands, PROK2. The mutations in PROKR2 (e.g., 607123.0001-607123.0005 and 607123.0008) were detected in heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation (607123.0001) was also heterozygous for a mutation in the KAL1 gene (300836.0012), suggesting possible digenic inheritance. The findings of Dode et al. (2006) demonstrated that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. Dode et al. (2006) noted that some of the mutations identified in the PROK2 and PROKR2 genes were detected in clinically unaffected individuals, indicating that additional genetic or nongenetic factors are involved in disease production. </p><p>In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, Cole et al. (2008) analyzed the PROKR2 and PROK2 genes and identified 10 and 5 different point mutations, respectively. All 10 mutations in PROKR2 were heterozygous (see, e.g., 607123.0001 and 607123.0006-607123.0009); 1 of the probands (see 607123.0007) also carried a heterozygous mutation in PROK2 (607002.0005). Of the 11 probands with a mutation in PROKR2, 7 had Kallmann syndrome and 4 had normosmic IHH; screening of 5 other HH-associated genes revealed no additional mutations. All mutant alleles appeared to decrease intracellular calcium mobilization; some also exhibited decreased MAPK signaling and decreased receptor expression. Cole et al. (2008) concluded that loss-of-function mutations in PROKR2 can cause both Kallmann syndrome and normosmic IHH. </p><p>By site-directed mutagenesis, Monnier et al. (2009) introduced human PROKR2 missense mutations identified in Kallmann syndrome patients into the mouse Prokr2 gene and tested their effects on signaling activity in transfected HEK293 cells by measuring intracellular calcium release upon ligand activation of the receptor. All mutated receptors except one (M323I; 607123.0005) had decreased signaling activities. The mutations L173R (607123.0001), W178S (607123.0008), and P290S impaired cell-surface targeting of the receptor. The Q210R mutation (607123.0002) abolished ligand binding. Five mutations (R85C, R85H (607123.0003), R164Q, R268C, V331M) presumably impaired G protein coupling of the receptor. When wildtype and mutant receptors were coexpressed in HEK293 cells, none of the intracellularly retained mutant receptors affected cell surface-targeting of the wildtype receptor, and none of the mutant receptors properly addressed at the plasma membrane affected wildtype receptor signaling activity. Monnier et al. (2009) concluded that their results argued against a dominant-negative effect of the mutations in vivo. </p><p>In 2 patients with anosmic hypogonadotropic hypogonadism (HH16; 614897) who were heterozygous for 2 different missense mutations in the SEMA3A gene (603961), Hanchate et al. (2012) also identified heterozygosity for a missense mutation in PROKR2. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Matsumoto et al. (2006) found that deletion of the Pkr2 gene in mice led to hypoplasia of the olfactory bulb and reproductive system, including testis, ovary, uterus, vagina, and mammary gland. In Pkr2 -/- mice, plasma levels of testosterone and follicle-stimulating hormone (see FSHB; 136530) were decreased, and the mRNA levels of gonadotropin-releasing hormone (see GNRH1; 152760) in the hypothalamus and luteinizing hormone (see LHB; 152780) and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that GNRH neurons were absent in the hypothalamus in Pkr2 -/- mice. Matsumoto et al. (2006) noted that the phenotype was similar to the clinical features of Kallmann syndrome. </p><p>Prosser et al. (2007) found that Prokr2 -/- mice demonstrated partially penetrant postnatal lethality and that surviving mice weighed significantly less than wildtype. Prokr2 -/- mice failed to breed, and they were hypokinetic and lost precision in the timing and onset of nocturnal locomotor activity compared to Prokr +/- mice and wildtype mice. Under both a light/dark cycle and continuous darkness, Prokr -/- mice showed a pronounced temporal redistribution of activity away from early to late circadian night, and they demonstrated disturbed regulation of core body temperature rhythm. In vitro studies of suprachiasmatic nucleus (SCN) slices showed normal circadian oscillation as demonstrated by bioluminescent real-time imaging. Prosser et al. (2007) concluded that Prokr2 is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night. </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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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA</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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PROKR2, LEU173ARG
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<br />
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SNP: rs74315416,
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gnomAD: rs74315416,
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ClinVar: RCV000022406, RCV000239273, RCV000516948, RCV001327944, RCV004782004
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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>Dode et al. (2006) identified a 518T-G transversion in exon 2 of the PROKR2 gene, resulting in a leu173-to-arg (L173R) substitution, in patients with Kallmann syndrome (HH3; 244200). The mutation was found in heterozygous state in a family and in 3 sporadic cases, in homozygous state in a sporadic case, and in compound heterozygous state with a Q210R mutation (607123.0002) in another family. In a sporadic case of Kallmann syndrome, Dode et al. (2006) found heterozygosity for L173R as well as heterozygosity for a mutation in the KAL1 gene (300836.0012), suggesting digenic inheritance. The L173R and Q210R mutations in the PROKR2 gene were not found in 500 ethnically matched (Caucasian) control alleles. </p><p>In 2 unrelated male patients with Kallmann syndrome, Cole et al. (2008) identified heterozygosity for the L173R mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the L173R mutant compared to wildtype in both assays. Both patients had complete absence of puberty with undetectable levels of luteinizing hormone (LH; 152780), and their sense of smell was below the fifth percentile on olfactory testing; MRI performed in 1 of the patients showed absence of the olfactory bulbs. Additional features included pes planus, pectus excavatum, and synkinesia in 1 patient and cryptorchidism in the other. </p><p>Monnier et al. (2009) performed functional analysis of the L173R mutation in HEK293 cells and demonstrated decreased signaling and impaired cell-surface targeting of the receptor compared to wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA</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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PROKR2, GLN210ARG
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<br />
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SNP: rs74315417,
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gnomAD: rs74315417,
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ClinVar: RCV000022407, RCV001797584
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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>For discussion of the gln210-to-arg (Q210R) mutation in the PROKR2 gene that was found in compound heterozygous state in patients with Kallmann syndrome (HH3; 244200) by Dode et al. (2006), see 607123.0001. </p><p>Monnier et al. (2009) performed functional analysis of the Q210R mutation in HEK293 cells and demonstrated that the mutation abolished ligand binding. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA</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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PROKR2, ARG85HIS
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<br />
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SNP: rs74315418,
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gnomAD: rs74315418,
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ClinVar: RCV000022408, RCV000498536, RCV001849252, RCV002254257, RCV003415639, RCV003991566, RCV004782005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a 254G-A transition in exon 1 of the PROKR2 gene, resulting in an arg85-to-his (R85H) substitution. They identified the same mutation in homozygous state in a sporadic case of Kallmann syndrome. </p><p>Monnier et al. (2009) performed functional analysis of the R85H mutation in HEK293 cells and observed decreased signaling activity compared to wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA</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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PROKR2, 1-BP DEL, 58C
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<br />
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SNP: rs587777834,
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gnomAD: rs587777834,
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ClinVar: RCV000022409, RCV000479789, RCV000623831, RCV001818122, RCV002288460, RCV004752681
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family with Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a 1-bp deletion (58delC) in exon 1 of the PROKR2 gene, causing a frameshift resulting in a premature termination codon (20fsTer43). In another family with Kallmann syndrome, they found the same mutation in compound heterozygous state with a 969G-A transition resulting in an M323I substitution (607123.0005). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROKR2, MET323ILE
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|
|
<br />
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|
|
SNP: rs74315419,
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|
|
|
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|
|
ClinVar: RCV000022410
|
|
|
|
|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the met323-to-ile (M323I) mutation in the PROKR2 gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism-3 with anosmia (HH3; 244200) by Dode et al. (2006), see 607123.0004. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 HYPOGONADOTROPIC HYPOGONADISM 3 WITHOUT ANOSMIA</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
PROKR2, ARG85CYS
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<br />
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|
|
SNP: rs141090506,
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|
|
gnomAD: rs141090506,
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|
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|
|
|
ClinVar: RCV000144712, RCV000239076, RCV000520900, RCV002247534, RCV003991574, RCV004752753
|
|
|
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|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient with normosmic hypogonadotropic hypogonadism (HH3; 244200), Cole et al. (2008) identified heterozygosity for a c.253C-T transition in the PROKR2 gene, resulting in an arg85-to-cys (R85C) substitution within the first intracellular loop. Functional analysis demonstrated significantly decreased intracellular calcium mobilization with the R85C mutant compared to wildtype. The mutation was not found in 346 control alleles; Dode et al. (2006) stated that they detected R85C in 1 of 500 Caucasian control alleles. The patient underwent partial puberty, with primary amenorrhea, but she had Tanner stage IV breast development and exhibited GnRH (152760)-induced luteinizing hormone (LH; see 152780) secretion in the setting of a low-normal estradiol level while still amenorrheic. She had a normal sense of smell on olfactory testing, and MRI showed normal olfactory bulbs. Both of her parents had delayed puberty; their mutation status was not reported. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
PROKR2, VAL115MET
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<br />
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|
|
SNP: rs138672528,
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|
|
gnomAD: rs138672528,
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|
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|
|
ClinVar: RCV000144713, RCV003390830
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient with Kallmann syndrome (HH3; 244200), Cole et al. (2008) identified a heterozygous c.343G-A transition in the PROKR2 gene, resulting in a val115-to-met (V115M) substitution within the first extracellular loop; in addition, a heterozygous mutation in the PROK2 gene (A24P; 607002.0005) was detected. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the V115M mutant compared to wildtype in both assays. The patient did not undergo puberty, and luteinizing hormone (LH; see 152780) was undetectable. Olfactory bulbs were absent on MRI. Other features included strabismus, hearing loss, short fourth metacarpal, pes planus, learning disability, and sleep disorder. </p>
|
|
</span>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
|
PROKR2, TRP178SER
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<br />
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|
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SNP: rs201835496,
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|
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gnomAD: rs201835496,
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|
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ClinVar: RCV000144714, RCV000870421
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with sporadic Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a c.533G-C transversion in exon 2 of the PROKR2 gene, resulting in a trp178-to-ser (W178S) substitution in the T4 domain. The mutation was not found in 500 ethnically matched (Caucasian) alleles. </p><p>In a male patient with normosmic hypogonadotropic hypogonadism, Cole et al. (2008) identified heterozygosity for the W178S mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the W178S mutant compared to wildtype in both assays. The patient did not undergo puberty and had a normal sense of smell on olfactory testing. He exhibited a pulsatile pattern of luteinizing hormone (LH; see 152780) and had elevated LH and follicle-stimulating hormone (FSH; see 136435) levels in the setting of hypogonadal testosterone levels. Cole et al. (2008) noted that the LH secretion pattern was hypergonadotropic, although not in the range of males with primary gonadal failure, suggesting a dual hypothalamic and gonadal defect that involved insufficient GNRH (152760) secretion as well as primary gonadal resistance. </p><p>Monnier et al. (2009) performed functional analysis of the W178S mutation in HEK293 cells and observed impaired cell-surface targeting of the receptor with the W178S mutant compared to wildtype. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 HYPOGONADOTROPIC HYPOGONADISM 3 WITHOUT ANOSMIA</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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PROKR2, ARG248GLN
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<br />
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SNP: rs376142095,
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gnomAD: rs376142095,
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ClinVar: RCV000144715, RCV001140929, RCV002514778
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a male patient with normosmic hypogonadotropic hypogonadism (HH3; 244200) who experienced reversal of his hypogonadism later in life, Cole et al. (2008) identified heterozygosity for a c.743G-A transition in the PROKR2 gene, resulting in an arg248-to-gln (R248Q) substitution within the last intracellular loop. The mutation was present in heterozygosity in the patient's unaffected father, but was not found in 346 control alleles. Functional analysis demonstrated decreased activity on calcium mobilization assay with the R248Q mutant compared to wildtype. The patient underwent partial puberty with some testicular growth (testicular volume, 6-7 ml) evident at the time of diagnosis. At 28 years of age, after discontinuation of testosterone therapy, he achieved fertility and sustained normal serum testosterone levels thereafter. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N.
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<strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong>
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J. Clin. Endocr. Metab. 93: 3551-3559, 2008.
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[PubMed: 18559922]
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[Full Text: https://doi.org/10.1210/jc.2007-2654]
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Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P.
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<strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong>
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PLoS Genet. 2: e175, 2006. Note: Electronic Article.
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[PubMed: 17054399]
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[Full Text: https://doi.org/10.1371/journal.pgen.0020175]
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Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others.
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<strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong>
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PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.
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[PubMed: 22927827]
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[Full Text: https://doi.org/10.1371/journal.pgen.1002896]
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Lin, D. C.-H., Bullock, C. M., Ehlert, F. J., Chen, J.-L., Tian, H., Zhou, Q.-Y.
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<strong>Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.</strong>
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J. Biol. Chem. 277: 19276-19280, 2002.
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[PubMed: 11886876]
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[Full Text: https://doi.org/10.1074/jbc.M202139200]
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Matsumoto, S., Yamazaki, C., Masumoto, K., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Takasaki, J., Kamohara, M., Matsuo, A., Ishii, H., Kobori, M., Katoh, M., Matsushime, H., Furuichi, K., Shigeyoshi, Y.
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<strong>Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2.</strong>
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Proc. Nat. Acad. Sci. 103: 4140-4145, 2006.
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[PubMed: 16537498]
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[Full Text: https://doi.org/10.1073/pnas.0508881103]
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Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P.
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<strong>PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.</strong>
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Hum. Molec. Genet. 18: 75-81, 2009.
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[PubMed: 18826963]
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[Full Text: https://doi.org/10.1093/hmg/ddn318]
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Prosser, H. M., Bradley, A., Chesham, J. E., Ebling, F. J. P., Hastings, M. H., Maywood, E. S.
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<strong>Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei.</strong>
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Proc. Nat. Acad. Sci. 104: 648-563, 2007.
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[PubMed: 17202262]
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[Full Text: https://doi.org/10.1073/pnas.0606884104]
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Marla J. F. O'Neill - updated : 10/23/2014<br>Marla J. F. O'Neill - updated : 10/28/2013<br>Marla J. F. O'Neill - updated : 9/27/2012<br>George E. Tiller - updated : 10/23/2009<br>Cassandra L. Kniffin - updated : 6/15/2007<br>Victor A. McKusick - updated : 11/21/2006<br>Patricia A. Hartz - updated : 5/3/2006
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