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Entry
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- *601538 - PROP PAIRED-LIKE HOMEOBOX 1; PROP1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601538</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601538">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000175325;t=ENST00000308304" 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=5626" 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=601538" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000175325;t=ENST00000308304" 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_006261" 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_006261" 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=601538" 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=03325&isoform_id=03325_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/PROP1" 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/3360342,3873238,3873240,46575725,119570780,311033413,1844084115" 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/O75360" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5626" 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=ENSG00000175325;t=ENST00000308304" 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=PROP1" 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=PROP1" 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+5626" 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/PROP1" 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:5626" 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/5626" 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=chr5&hgg_gene=ENST00000308304.2&hgg_start=177992235&hgg_end=177996242&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9455" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/prop1" 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=601538[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=601538[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000175325" 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.gwascentral.org/search?q=PROP1" 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=PROP1" 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=PROP1&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/PA33808" 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:9455" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0052532.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:109330" 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/PROP1#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:109330" 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/5626/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=5626" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006778;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-081107-40" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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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=PROP1&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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601538
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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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PROP PAIRED-LIKE HOMEOBOX 1; PROP1
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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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PROPHET OF PIT1, PAIRED-LIKE HOMEODOMAIN TRANSCRIPTION FACTOR
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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=PROP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PROP1</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/5/818?start=-3&limit=10&highlight=818">5q35.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:177992235-177996242&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'})">5:177,992,235-177,996,242</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/5/818?start=-3&limit=10&highlight=818">
|
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5q35.3
|
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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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Pituitary hormone deficiency, combined, 2
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/262600"> 262600 </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 recessive">AR</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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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>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601538" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601538" 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.">
|
|
<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="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<p>PROP1 is a pituitary-specific paired-like homeodomain transcription factor that plays a crucial role in the proper development of somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs (summary by <a href="#9" class="mim-tip-reference" title="Duquesnoy, P., Roy, A., Dastot, F., Ghali, I., Teinturier, C., Netchine, I., Cacheux, V., Hafez, M., Salah, N., Chaussain, J.-L., Goossens, M., Bougneres, P., Amselem, S. <strong>Human Prop-1: cloning, mapping, genomic structure: mutations in familial combined pituitary hormone deficiency.</strong> FEBS Lett. 437: 216-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9824293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9824293</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01234-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9824293">Duquesnoy et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9824293" 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="#9" class="mim-tip-reference" title="Duquesnoy, P., Roy, A., Dastot, F., Ghali, I., Teinturier, C., Netchine, I., Cacheux, V., Hafez, M., Salah, N., Chaussain, J.-L., Goossens, M., Bougneres, P., Amselem, S. <strong>Human Prop-1: cloning, mapping, genomic structure: mutations in familial combined pituitary hormone deficiency.</strong> FEBS Lett. 437: 216-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9824293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9824293</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01234-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9824293">Duquesnoy et al. (1998)</a> cloned a human PROP1 cDNA, which encodes a deduced 226-amino acid protein that shares 73% overall sequence identity with mouse Prop1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9824293" 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>PROP1 mRNA is expressed in the developing pituitary gland before PIT1 mRNA expression and maximum expression are observed at e12.0. After e14.5, PROP1 mRNA expression rapidly decreases, and only trace amounts of mRNA are detectable in adult mouse pituitary (<a href="#29" class="mim-tip-reference" title="Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S., Norman, D. J., O'Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P., Zuo, L., Gleiberman, A. S., Andersen, B., Beamer, W. G., Rosenfeld, M. G. <strong>Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.</strong> Nature 384: 327-333, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8934515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8934515</a>] [<a href="https://doi.org/10.1038/384327a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8934515">Sornson et al., 1996</a>). <a href="#19" class="mim-tip-reference" title="Nakamura, Y., Usui, T., Mizuta, H., Murabe, H., Muro, S., Suda, M., Tanaka, K., Tanaka, I., Shimatsu, A., Nakao, K. <strong>Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans.</strong> J. Clin. Endocr. Metab. 84: 1414-1419, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199788</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199788">Nakamura et al. (1999)</a> studied human PROP1 expression in adult pituitary and pituitary adenomas. Human PROP1 transcripts were detected in normal adult pituitary by Northern blot analysis, and in all pituitary adenomas examined by RT-PCR analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10199788+8934515" 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="#9" class="mim-tip-reference" title="Duquesnoy, P., Roy, A., Dastot, F., Ghali, I., Teinturier, C., Netchine, I., Cacheux, V., Hafez, M., Salah, N., Chaussain, J.-L., Goossens, M., Bougneres, P., Amselem, S. <strong>Human Prop-1: cloning, mapping, genomic structure: mutations in familial combined pituitary hormone deficiency.</strong> FEBS Lett. 437: 216-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9824293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9824293</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01234-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9824293">Duquesnoy et al. (1998)</a> determined that the PROP1 gene has at least 3 exons and spans less than 4 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9824293" 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>There is considerable homology of synteny between mouse chromosome 11 and human 5q; the linkage of the df (Prop1) gene to the interleukin cluster (e.g., IL3, <a href="/entry/147740">147740</a>) on chromosome 11 in the mouse suggested that the human PROP1 gene is located on human chromosome 5q. <a href="#28" class="mim-tip-reference" title="Rosenfeld, M. G., Wu, W. <strong>Personal Communication.</strong> San Diego, Calif. 1/23/1998."None>Rosenfeld and Wu (1998)</a> confirmed that PROP1 is located on 5q by radiation hybrid mapping.</p><p>By fluorescence in situ hybridization, <a href="#9" class="mim-tip-reference" title="Duquesnoy, P., Roy, A., Dastot, F., Ghali, I., Teinturier, C., Netchine, I., Cacheux, V., Hafez, M., Salah, N., Chaussain, J.-L., Goossens, M., Bougneres, P., Amselem, S. <strong>Human Prop-1: cloning, mapping, genomic structure: mutations in familial combined pituitary hormone deficiency.</strong> FEBS Lett. 437: 216-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9824293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9824293</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01234-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9824293">Duquesnoy et al. (1998)</a> mapped the PROP1 gene to chromosome 5q35. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9824293" 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>Inactivating mutations in PROP1 perturb ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes. These developmental defects result in deficiencies of luteinizing hormone (LH; <a href="/entry/152780">152780</a>), follicle-stimulating hormone (FSH; <a href="/entry/136530">136530</a>), growth hormone (GH; <a href="/entry/139250">139250</a>), prolactin (PRL; <a href="/entry/176760">176760</a>), and thyroid-stimulating hormone (TSH; <a href="/entry/188540">188540</a>).</p><p><a href="#32" class="mim-tip-reference" title="Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G. <strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong> Nature Genet. 18: 147-149, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462743</a>] [<a href="https://doi.org/10.1038/ng0298-147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462743">Wu et al. (1998)</a> identified 4 families in which combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>) was produced by homozygosity or compound heterozygosity for inactivating mutations of the PROP1 gene. These mutations in the PROP1 gene resulted in a gene product with reduced DNA binding and transcriptional activation ability in comparison to the product of the murine df mutation (e.g., <a href="#0002">601538.0002</a>). In contrast to individuals with mutations in the human homolog of the mouse Pit1 gene, POU1F1 (<a href="/entry/173110">173110</a>), those with PROP1 mutations cannot produce luteinizing hormone or follicle-stimulating hormone at a sufficient level and do not enter puberty spontaneously. The results identified a major cause of combined pituitary hormone deficiency in humans and suggested a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes, and caudomedial thyrotropes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462743" 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 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, <a href="#10" class="mim-tip-reference" title="Fluck, C., Deladoey, J., Rutishauser, K., Eble, A., Marti, U., Wu, W., Mullis, P. E. <strong>Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of arg to cys at codon 120 (R120C).</strong> J. Clin. Endocr. Metab. 83: 3727-3734, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768691</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768691">Fluck et al. (1998)</a> identified homozygosity for the R120C mutation in the PROP1 gene (<a href="#0001">601538.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9768691" 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>Whereas a variety of PROP1 mutations have been reported, <a href="#6" class="mim-tip-reference" title="Cogan, J. D., Wu, W., Phillips, J. A., III, Arnhold, I. J. P., Agapito, A., Fofanova, O. V., Osorio, M. G. F., Bircan, I., Moreno, A., Mendonca, B. B. <strong>The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 83: 3346-3349, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9745452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9745452</a>] [<a href="https://doi.org/10.1210/jcem.83.9.5142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9745452">Cogan et al. (1998)</a> found by analysis of 10 independent CPHD kindreds that the 301delAG allele (<a href="#0002">601538.0002</a>) constitutes a major portion, perhaps 55%, of PROP1 mutant alleles. <a href="#6" class="mim-tip-reference" title="Cogan, J. D., Wu, W., Phillips, J. A., III, Arnhold, I. J. P., Agapito, A., Fofanova, O. V., Osorio, M. G. F., Bircan, I., Moreno, A., Mendonca, B. B. <strong>The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 83: 3346-3349, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9745452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9745452</a>] [<a href="https://doi.org/10.1210/jcem.83.9.5142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9745452">Cogan et al. (1998)</a> also concluded from analysis of a tightly linked polymorphic marker that the 301delAG allele may be a recurring mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9745452" 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 individuals with CPHD2 (Hanhart dwarfism) from the isolated community on the Island of Krk in the Adriatic Sea, <a href="#13" class="mim-tip-reference" title="Krzisnik, C., Kolacio, Z., Battelino, T., Brown, M., Parks, J. S., Laron, Z. <strong>The 'little people' of the Island of Krk - revisited: etiology of hypopituitarism revealed.</strong> J. Endocr. Genet. 1: 9-19, 1999."None>Krzisnik et al. (1999)</a> identified homozygosity for a frameshift mutation in the PROP1 gene (<a href="#0014">601538.0014</a>).</p><p><a href="#19" class="mim-tip-reference" title="Nakamura, Y., Usui, T., Mizuta, H., Murabe, H., Muro, S., Suda, M., Tanaka, K., Tanaka, I., Shimatsu, A., Nakao, K. <strong>Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans.</strong> J. Clin. Endocr. Metab. 84: 1414-1419, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199788</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199788">Nakamura et al. (1999)</a> sequenced PROP1 cDNAs from pituitary adenomas. They found that the amino acid sequence of cloned human PROP1 cDNA was identical to the reported sequence, except for an ala142-to-thr substitution. They concluded that this substitution is a polymorphism because it did not alter transcriptional activity, and 7 of 28 (25%) alleles encoded ala. Because sequence analysis of PROP1 cDNAs from human pituitary adenomas only revealed 5 silent nucleic acid substitutions, <a href="#19" class="mim-tip-reference" title="Nakamura, Y., Usui, T., Mizuta, H., Murabe, H., Muro, S., Suda, M., Tanaka, K., Tanaka, I., Shimatsu, A., Nakao, K. <strong>Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans.</strong> J. Clin. Endocr. Metab. 84: 1414-1419, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199788</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199788">Nakamura et al. (1999)</a> concluded that PROP1 mutations do not represent a frequent mechanism of human pituitary tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Deladoey, J., Fluck, C., Buyukgebiz, A., Kuhlmann, B. V., Eble, A., Hindmarsh, P. C., Wu, W., Mullis, P. E. <strong>'Hot Spot' in the PROP1 gene responsible for combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 84: 1645-1650, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323394</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323394">Deladoey et al. (1999)</a> screened families and patients suffering from different forms of CPHD for PROP1 gene alterations to define possible hotspots and the frequency of the different gene alterations found. Of 73 subjects (36 families) analyzed, they identified 35 patients, belonging to 18 unrelated families, with CPHD caused by a PROP1 gene defect. The PROP1 gene alterations included 3 missense mutations, 2 frameshift mutations, and 1 splice site mutation. The 2 reported frameshift mutations could be caused by any 2-bp GA or AG deletion at either the 148-GGA-GGG-153 or 295-CGA-GAG-AGT-303 position. As any combination of a GA or AG deletion yields the same sequencing data, the authors called the frameshift mutations 149delGA and 296delGA, respectively. All but 1 mutation were located in the homeodomain of the PROP1 gene. <a href="#8" class="mim-tip-reference" title="Deladoey, J., Fluck, C., Buyukgebiz, A., Kuhlmann, B. V., Eble, A., Hindmarsh, P. C., Wu, W., Mullis, P. E. <strong>'Hot Spot' in the PROP1 gene responsible for combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 84: 1645-1650, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323394</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323394">Deladoey et al. (1999)</a> concluded that 3 tandem repeats of the dinucleotides GA at location 296 to 302 in the PROP1 gene represent a hotspot for CPHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323394" 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="#30" class="mim-tip-reference" title="Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T. <strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong> J. Clin. Endocr. Metab. 86: 4529-4535, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549703">Vallette-Kasic et al. (2001)</a> screened the PROP1 gene in 23 CPHD patients and identified homozygosity or compound heterozygosity for 4 mutations in 9 patients from 8 unrelated families. All mutations were located in exon 2 and affected only 2 different sites (see <a href="#0005">601538.0005</a> and <a href="#0009">601538.0009</a>-<a href="#0011">601538.0011</a>). <a href="#30" class="mim-tip-reference" title="Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T. <strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong> J. Clin. Endocr. Metab. 86: 4529-4535, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549703">Vallette-Kasic et al. (2001)</a> stated that, in keeping with previous reports, they found no correlation between phenotype and genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549703" 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="#25" class="mim-tip-reference" title="Reynaud, R., Chadli-Chaieb, M., Vallette-Kasic, S., Barlier, A., Sarles, J., Pellegrini-Bouiller, I., Enjalbert, A., Chaieb, L., Brue, T. <strong>A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.</strong> J. Clin. Endocr. Metab. 89: 5779-5786, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531542</a>] [<a href="https://doi.org/10.1210/jc.2003-032124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531542">Reynaud et al. (2004)</a> reported a homozygous R73C mutation of PROP1 (<a href="#0010">601538.0010</a>) in all 10 patients studied from a large consanguineous Tunisian kindred with CPHD; heterozygosity for the mutation was found in 6 unaffected parents or sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531542" 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 retrospective longitudinal analysis of 9 CPHD patients with known PROP1 mutations, primarily involving homozygous or compound heterozygous deletions (e.g., <a href="#0002">601538.0002</a> and <a href="#0008">601538.0008</a>), <a href="#4" class="mim-tip-reference" title="Bottner, A., Keller, E., Kratzsch, J., Stobbe, H., Weigel, J. F. W., Keller, A., Hirsch, W., Kiess, W., Blum, W. F., Pfaffle, R. W. <strong>PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis.</strong> J. Clin. Endocr. Metab. 89: 5256-5265, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472232</a>] [<a href="https://doi.org/10.1210/jc.2004-0661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15472232">Bottner et al. (2004)</a> found that all patients developed at least partial adrenal insufficiency requiring hydrocortisone therapy. The authors concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 brothers from a consanguineous family of Tunisian descent with CPHD, who initially presented as cases of isolated hypogonadotropic hypogonadism, <a href="#24" class="mim-tip-reference" title="Reynaud, R., Barlier, A., Vallette-Kasic, S., Saveanu, A., Guillet, M.-P., Simonin, G., Enjalbert, A., Valensi, P., Brue, T. <strong>An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.</strong> J. Clin. Endocr. Metab. 90: 4880-4887, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15941866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15941866</a>] [<a href="https://doi.org/10.1210/jc.2005-0119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15941866">Reynaud et al. (2005)</a> identified homozygosity for a nonsense mutation in the PROP1 gene (W194X; <a href="#0013">601538.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15941866" 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="#22" class="mim-tip-reference" title="Osorio, M. G. F., Marui, S., Jorge, A. A. L., Latronico, A. C., Lo, L. S. S., Leite, C. C., Estefan, V., Mendonca, B. B., Arnhold, I. J. P. <strong>Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes.</strong> J. Clin. Endocr. Metab. 87: 5076-5084, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414875</a>] [<a href="https://doi.org/10.1210/jc.2001-011936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414875">Osorio et al. (2002)</a> stated that the pathogenesis of pituitary stalk interruption and ectopic posterior lobe, frequently observed on MRI in patients with GH deficiency (see <a href="/entry/262400">262400</a>), was controversial. They performed pituitary stimulation tests and MRI, and studied the PROP1, GH1, and GHRHR (<a href="/entry/139191">139191</a>) genes, in 76 patients with GHD. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequencies of consanguinity (P less than 0.001) and familial cases (P less than 0.05) and lower frequency of breech delivery or hypoxemia at birth (P less than 0.005). On MRI, all patients with mutations had an intact pituitary stalk, whereas it was interrupted or thin in 74% without mutations (P less than 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations versus 13% without mutations (P less than 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP1 and PIT1 mutations and suggestive of hypothalamic origin in 81% without mutations. PROP1, GH1, and GHRHR mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. <a href="#22" class="mim-tip-reference" title="Osorio, M. G. F., Marui, S., Jorge, A. A. L., Latronico, A. C., Lo, L. S. S., Leite, C. C., Estefan, V., Mendonca, B. B., Arnhold, I. J. P. <strong>Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes.</strong> J. Clin. Endocr. Metab. 87: 5076-5084, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414875</a>] [<a href="https://doi.org/10.1210/jc.2001-011936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414875">Osorio et al. (2002)</a> concluded that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiologic diagnosis of GHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12414875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The Snell dwarf mouse (dw) has a mutation in the Pit1 gene (POU1F1; <a href="/entry/173110">173110</a>) which encodes pituitary-specific transcription factor-1. Mutations in the human homolog, PIT1, are the basis of combined pituitary hormone deficiency in humans (e.g., <a href="/entry/173110#0001">173110.0001</a>). Reasoning that the Snell dwarf might represent a point mutation, <a href="#15" class="mim-tip-reference" title="Li, S., Crenshaw, E. B., III, Rawson, E. J., Simmons, D. M., Swanson, L. W., Rosenfeld, M. G. <strong>Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene Pit-1.</strong> Nature 347: 528-533, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1977085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1977085</a>] [<a href="https://doi.org/10.1038/347528a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1977085">Li et al. (1990)</a> did studies which demonstrated a G-to-T change that converted the tryptophan residue in the POU-homeodomain (trp261) to cysteine. Neither mRNA nor protein was detected in either of the 2 types of dwarf mice. They also demonstrated that the Ames dwarf mouse (df) has a nonallelic mutation that maps to mouse chromosome 11 and is associated with absence of detectable Pit1 gene expression. Thus, the Ames mutation df appeared to be epistatic to the Pit1 locus. The df locus may be involved in the regulation of Pit1, or perhaps in conjunction with Pit1, in the specification and/or maintenance of the 3 specific pituitary cell types affected by the mutation. <a href="#2" class="mim-tip-reference" title="Andersen, B., Pearse, R. V., II, Jenne, K., Sornson, M., Lin, S.-C., Bartke, A., Rosenfeld, M. G. <strong>The Ames dwarf gene is required for Pit-1 gene activation.</strong> Dev. Biol. 172: 495-503, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612966</a>] [<a href="https://doi.org/10.1006/dbio.1995.8040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8612966">Andersen et al. (1995)</a> pointed out that the Ames dwarf exhibits a phenotype identical to that of the Pit1-mutated mice. Their studies indicated that initial activation of the Pit1 gene is deficient in the Ames dwarf. This suggested that the df gene is required for activation of the Pit1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1977085+8612966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S., Norman, D. J., O'Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P., Zuo, L., Gleiberman, A. S., Andersen, B., Beamer, W. G., Rosenfeld, M. G. <strong>Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.</strong> Nature 384: 327-333, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8934515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8934515</a>] [<a href="https://doi.org/10.1038/384327a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8934515">Sornson et al. (1996)</a> isolated the murine gene that is mutant in the Ames dwarf (df) by positional cloning and identified a tissue-specific, 'paired'-like homeodomain transcription factor, which they termed 'Prophet of Pit1' (Prop1). The df phenotype resulted from an apparent failure of initial determination of the Pit1 lineage required for production of growth hormone, prolactin, or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit1 gene expression. The results suggested to <a href="#29" class="mim-tip-reference" title="Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S., Norman, D. J., O'Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P., Zuo, L., Gleiberman, A. S., Andersen, B., Beamer, W. G., Rosenfeld, M. G. <strong>Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.</strong> Nature 384: 327-333, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8934515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8934515</a>] [<a href="https://doi.org/10.1038/384327a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8934515">Sornson et al. (1996)</a> that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8934515" 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>Analysis of double heterozygotes and double mutants by <a href="#12" class="mim-tip-reference" title="Gage, P. J., Brinkmeier, M. L., Scarlett, L. M., Knapp, L. T., Camper, S. A., Mahon, K. A. <strong>The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation.</strong> Molec. Endocr. 10: 1570-1581, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8961267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8961267</a>] [<a href="https://doi.org/10.1210/mend.10.12.8961267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8961267">Gage et al. (1996)</a> indicated that the df and dw genes act sequentially in the same genetic pathway. Double heterozygotes had no reduction in growth rate or final adult size. Double homozygotes had essentially the same phenotype as the single mutants and were recovered at the predicted frequency, indicating that there are no previously unrecognized, redundant functions of the 2 genes. The df mutants failed to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands was reduced by e14.5, while Pit1dw mutants downregulate Rpx appropriately and exhibit normal cell proliferation up to e14.5. These occurrences suggest that df acts earlier in the differentiation pathway than Pit1 to regulate pituitary ontogeny. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8961267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Brown-Borg, H. M., Borg, K. E., Meliska, C. J., Bartke, A. <strong>Dwarf mice and the ageing process. (Letter)</strong> Nature 384: 33 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900272</a>] [<a href="https://doi.org/10.1038/384033a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900272">Brown-Borg et al. (1996)</a> noted that Ames dwarf mice (df/df) are of normal body size at birth but postnatal growth is severely retarded and the body size of adult animals is approximately one-third of normal. The authors found, however, that df/df mice lived much longer than normal mice, with a difference in average life span being more than 350 days for males and more than 470 days for females. Two df/df females reached the remarkable age of 4 years. These findings were particularly striking because Ames dwarfs exhibit some characteristics of reduced immune function and the animals were maintained in a conventional environment and fed lab chow and tap water without restriction. <a href="#5" class="mim-tip-reference" title="Brown-Borg, H. M., Borg, K. E., Meliska, C. J., Bartke, A. <strong>Dwarf mice and the ageing process. (Letter)</strong> Nature 384: 33 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900272</a>] [<a href="https://doi.org/10.1038/384033a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900272">Brown-Borg et al. (1996)</a> speculated on the mechanism of the increased survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900272" 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="Cushman, L. J., Watkins-Chow, D. E., Brinkmeier, M. L., Raetzman, L. T., Radak, A. L., Lloyd, R. V., Camper, S. A. <strong>Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility.</strong> Hum. Molec. Genet. 10: 1141-1153, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371507</a>] [<a href="https://doi.org/10.1093/hmg/10.11.1141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371507">Cushman et al. (2001)</a> generated transgenic mice which constitutively expressed Prop1. The terminal differentiation of pituitary gonadotropes was delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurred normally, but thyrotrope function was impaired, resulting in mild hypothyroidism. Aged mice exhibited defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke cleft cysts and tumors. The authors concluded that silencing Prop1 is important for normal pituitary development and function, and that gain-of-function mutations in PROP1 could contribute to common human pituitary endocrinopathies and tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371507" 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 reducing the number of calories consumed by Ames dwarf mice, <a href="#3" class="mim-tip-reference" title="Bartke, A., Wright, J. C., Mattison, J. A., Ingram, D. K., Miller, R. A., Roth, G. S. <strong>Extending the lifespan of long-lived mice.</strong> Nature 414: 412 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719795</a>] [<a href="https://doi.org/10.1038/35106646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719795">Bartke et al. (2001)</a> investigated whether the longevity associated with Ames dwarf mice is influenced by similar or independent mechanisms to the longevity associated with caloric restrictions. <a href="#3" class="mim-tip-reference" title="Bartke, A., Wright, J. C., Mattison, J. A., Ingram, D. K., Miller, R. A., Roth, G. S. <strong>Extending the lifespan of long-lived mice.</strong> Nature 414: 412 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719795</a>] [<a href="https://doi.org/10.1038/35106646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719795">Bartke et al. (2001)</a> found that 70% caloric restriction conferred a further life span increase in the dwarf, indicating that the 2 factors may act through different pathways. Survival plots indicated that although both dwarfism and calorie restriction extend longevity, the effect of reduced food intake is associated primarily with a change in the slope of the survival curve (i.e., it reduces the rate of age-related mortality), whereas the effect of dwarfism mainly reflects a shift in the age at which the age-dependent increase in mortality risk first becomes appreciable. Calorie restriction, therefore, seems to decelerate aging, whereas the Prop1(df) allele seems to delay it. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Nasonkin, I. O., Ward, R. D., Raetzman, L. T., Seasholtz, A. F., Saunders, T. L., Gillespie, P. J., Camper, S. A. <strong>Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice.</strong> Hum. Molec. Genet. 13: 2727-2735, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459176</a>] [<a href="https://doi.org/10.1093/hmg/ddh311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459176">Nasonkin et al. (2004)</a> showed that deletion of Prop1 in mice caused severe pituitary hypoplasia with failure of the entire Pit1 lineage and delayed gonadotrope development. Pituitary hormone deficiencies caused secondary endocrine problems and a high rate of perinatal mortality due to respiratory distress. Lung atelectasis in mutants correlated with reduced levels of NKX2.1 (TITF1; <a href="/entry/600635">600635</a>) and surfactant (SFTPA1; <a href="/entry/178630">178630</a>). Lethality of mice homozygous for either the null allele or a spontaneous hypomorphic allele was strongly influenced by genetic background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The mouse gene Prop1, which is mutant in the Ames dwarf (df), was isolated by <a href="#29" class="mim-tip-reference" title="Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S., Norman, D. J., O'Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P., Zuo, L., Gleiberman, A. S., Andersen, B., Beamer, W. G., Rosenfeld, M. G. <strong>Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.</strong> Nature 384: 327-333, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8934515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8934515</a>] [<a href="https://doi.org/10.1038/384327a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8934515">Sornson et al. (1996)</a>. The first humans with CPHD due to PROP1 defects were reported by <a href="#32" class="mim-tip-reference" title="Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G. <strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong> Nature Genet. 18: 147-149, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462743</a>] [<a href="https://doi.org/10.1038/ng0298-147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462743">Wu et al. (1998)</a>. The human PROP1 mutations resulted in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the Ames dwarf mutation (e.g., <a href="#0002">601538.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9462743+8934515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family with 2 brothers and a sister with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>), <a href="#32" class="mim-tip-reference" title="Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G. <strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong> Nature Genet. 18: 147-149, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462743</a>] [<a href="https://doi.org/10.1038/ng0298-147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462743">Wu et al. (1998)</a> identified a C-to-T transition resulting in an arg120-to-cys amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462743" 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 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, <a href="#10" class="mim-tip-reference" title="Fluck, C., Deladoey, J., Rutishauser, K., Eble, A., Marti, U., Wu, W., Mullis, P. E. <strong>Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of arg to cys at codon 120 (R120C).</strong> J. Clin. Endocr. Metab. 83: 3727-3734, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768691</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768691">Fluck et al. (1998)</a> identified homozygosity for the R120C mutation in the PROP1 gene. The authors noted that there was variability in the phenotype, even among these patients with the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9768691" 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> rs193922688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193922688;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/rs193922688?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=rs193922688" 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=rs193922688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In each of 2 separate families, <a href="#32" class="mim-tip-reference" title="Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G. <strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong> Nature Genet. 18: 147-149, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462743</a>] [<a href="https://doi.org/10.1038/ng0298-147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462743">Wu et al. (1998)</a> showed that 3 sibs with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>) carried a 2-bp deletion (301A and 302G) leading to a frameshift in the coding sequence starting at codon 101 and premature termination at codon 109. The truncation resulted in the loss of the DNA-binding homeodomain and the C-terminal transactivation domain of PROP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462743" 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="Cogan, J. D., Wu, W., Phillips, J. A., III, Arnhold, I. J. P., Agapito, A., Fofanova, O. V., Osorio, M. G. F., Bircan, I., Moreno, A., Mendonca, B. B. <strong>The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 83: 3346-3349, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9745452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9745452</a>] [<a href="https://doi.org/10.1210/jcem.83.9.5142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9745452">Cogan et al. (1998)</a> determined the frequency of the 301delAG mutation in exon 2 of PROP1 in 10 independently ascertained combined pituitary hormone deficiency (CPHD) kindreds and 21 sporadic cases of CPHD from 8 different countries. They found that 55% (11 of 20) of the PROP1 alleles were 301delAG in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles in the 21 sporadic cases were 301delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given thyrotropin-releasing hormone stimulation tests) was 50% (3 of 6) in the CPHD cases with pituitary defects, and 0% (0 of 34) in the CPHD cases with hypothalamic defects. Using whole genome radiation hybrid analysis, they localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. The authors concluded that analysis of this marker in affected subjects with the 301delAG mutation suggests that rather than being inherited from a common founder, 301delAG may be a recurring mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9745452" 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 females with CPHD, <a href="#17" class="mim-tip-reference" title="Mendonca, B. B., Osorio, M. G. F., Latronico, A. C., Estefan, V., Lo, L. S. S., Arnhold, I. J. P. <strong>Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene.</strong> J. Clin. Endocr. Metab. 84: 942-945, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10084575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10084575</a>] [<a href="https://doi.org/10.1210/jcem.84.3.5537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10084575">Mendonca et al. (1999)</a> identified homozygosity for the 301AG deletion in the PROP1 gene. MRI findings changed over time in these patients, and 1 had partial cortisol deficiency. The authors concluded that a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced T1 signal on MRI suggests PROP1 deficiency; that pituitary morphology can change during follow-up of patients with PROP1 mutations; and that hormonal deficiencies associated with PROP1 mutations can include the adrenal axis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10084575" 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 10 CPHD patients from a large Brazilian kindred, 9 of whom were born of consanguineous marriages, <a href="#23" class="mim-tip-reference" title="Pernasetti, F., Toledo, S. P. A., Vasilyev, V. V., Hayashida, C. Y., Cogan, J. D., Ferrari, C., Lourenco, D. M., Mellon, P. L. <strong>Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene.</strong> J. Clin. Endocr. Metab. 85: 390-397, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10634415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10634415</a>] [<a href="https://doi.org/10.1210/jcem.85.1.6324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10634415">Pernasetti et al. (2000)</a> identified homozygosity for the 301AG deletion in PROP1. The authors observed ACTH/cortisol insufficiency in 5 of 6 of the older patients and in one 11-year-old patient, and suggested that the phenotype of this mutation includes late-onset adrenal insufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10634415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Riepe, F. G., Partsch, C.-J., Blankenstein, O., Monig, H., Pfaffle, R. W., Sippell, W. G. <strong>Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.</strong> J. Clin. Endocr. Metab. 86: 4353-4357, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549674</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549674">Riepe et al. (2001)</a> found this mutation in compound heterozygosity with 150delA (<a href="#0008">601538.0008</a>) in 2 brothers with typical manifestations of PROP1 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The 301-302delAG frameshift mutation was found in homozygous state as the cause of the CPHD in the Hutterite cases reported by <a href="#16" class="mim-tip-reference" title="McKusick, V. A., Rimoin, D. L. <strong>General Tom Thumb and other midgets.</strong> Sci. Am. 217(1): 102-111, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6046325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6046325</a>] [<a href="https://doi.org/10.1038/scientificamerican0767-102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6046325">McKusick and Rimoin (1967)</a> (<a href="#18" class="mim-tip-reference" title="Mosely, C. T., Phillips, J. A., III, Rimoin, D. L. <strong>Genetic disorders of the pituitary gland. In: Rimoin, D. L.; Connor, J. M.; Pyeritz, R. E.; Korf, B. R. (eds.): Emery and Rimoin's Principles and Practices of Medical Genetics. (4th ed.)</strong> London: Churchill Livingston 2002. P. 2153. Note: Fig. 80.3."None>Mosely et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6046325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 adult sibs, aged 18 to 25 years, with short stature, hypothyroidism, and lack of pubertal maturation, <a href="#14" class="mim-tip-reference" title="Lee, J. K., Zhu, Y.-S., Cordero, J. J., Cai, L.-Q., Labour, I., Herrera, C., Imperato-McGinley, J. <strong>Long-term growth hormone therapy in adult results in significant linear growth in siblings with a PROP-1 gene mutation.</strong> J. Clin. Endocr. Metab. 89: 4850-4856, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472175</a>] [<a href="https://doi.org/10.1210/jc.2003-031816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15472175">Lee et al. (2004)</a> identified homozygosity for the 301AG deletion in PROP1. All 3 patients responded with a dramatic increase in linear growth to treatment with GH and thyroid replacement administered prior to beginning sex steroid replacement therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472175" 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> rs121917840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917840;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/rs121917840?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=rs121917840" 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=rs121917840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a sporadic case of combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>), <a href="#32" class="mim-tip-reference" title="Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G. <strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong> Nature Genet. 18: 147-149, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462743</a>] [<a href="https://doi.org/10.1038/ng0298-147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462743">Wu et al. (1998)</a> identified compound heterozygosity for mutations in the PROP1 gene. A 2-bp deletion (301delAG; <a href="#0002">601538.0002</a>) was inherited from the mother; the paternal allele carried a T-to-A transversion at nucleotide 349, resulting in a phe117-to-ile amino acid substitution. Magnetic resonance imaging revealed hypocellular pituitary in this patient. This patient and the affected individuals homozygous for the 301delAG deletion failed to respond to growth hormone-releasing hormone (GHRH; <a href="/entry/139190">139190</a>), thyrotropin-releasing hormone (TRH; <a href="/entry/613879">613879</a>), and LH-releasing hormone (LHRH; <a href="/entry/152760">152760</a>) stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462743" 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">rs587776681 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776681;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=rs587776681" 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=rs587776681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 Russian children with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>), including a brother and sister and 3 unrelated children, <a href="#11" class="mim-tip-reference" title="Fofanova, O., Takamura, N., Kinoshita, E., Parks, J. S., Brown, M. R., Peterkova, V. A., Evgrafov, O. V., Goncharov, N. P., Bulatov, A. A., Dedov, I. I., Yamashita, S. <strong>Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 83: 2601-2604, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9661653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9661653</a>] [<a href="https://doi.org/10.1210/jcem.83.7.5094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9661653">Fofanova et al. (1998)</a> identified compound heterozygosity for 2 2-bp deletions in the PROP1 gene, 149delGA and 296delGA (<a href="#0005">601538.0005</a>), both of which result in premature termination of the protein due to a stop codon at residue 109. Another affected brother and sister and an unrelated girl with CPHD were homozygous for 149delGA. All parents were of normal stature and each was heterozygous for a wildtype allele and 1 of the deletions, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9661653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008566 OR RCV000030379 OR RCV000517269 OR RCV002254517 OR RCV004755724" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008566, RCV000030379, RCV000517269, RCV002254517, RCV004755724" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008566...</a>
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<p>For discussion of the 2-bp deletion in the PROP1 gene (296delGA) that was found in compound heterozygous state in patients with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>) by <a href="#11" class="mim-tip-reference" title="Fofanova, O., Takamura, N., Kinoshita, E., Parks, J. S., Brown, M. R., Peterkova, V. A., Evgrafov, O. V., Goncharov, N. P., Bulatov, A. A., Dedov, I. I., Yamashita, S. <strong>Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 83: 2601-2604, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9661653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9661653</a>] [<a href="https://doi.org/10.1210/jcem.83.7.5094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9661653">Fofanova et al. (1998)</a>, see <a href="#0004">601538.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9661653" 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 8 patients from a large Dominican kindred with CPHD2, the largest such family reported to that time, <a href="#27" class="mim-tip-reference" title="Rosenbloom, A. L., Almonte, A. S., Brown, M. R., Fisher, D. A., Baumbach, L., Parks, J. S. <strong>Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.</strong> J. Clin. Endocr. Metab. 84: 50-57, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920061</a>] [<a href="https://doi.org/10.1210/jcem.84.1.5366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9920061">Rosenbloom et al. (1999)</a> identified homozygosity for the 296delGA mutation in the PROP1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Deladoey, J., Fluck, C., Buyukgebiz, A., Kuhlmann, B. V., Eble, A., Hindmarsh, P. C., Wu, W., Mullis, P. E. <strong>'Hot Spot' in the PROP1 gene responsible for combined pituitary hormone deficiency.</strong> J. Clin. Endocr. Metab. 84: 1645-1650, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323394</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323394">Deladoey et al. (1999)</a> found this mutation in patients from distinct genetic backgrounds and described the site of the mutation as one of high mutability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323394" 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="#30" class="mim-tip-reference" title="Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T. <strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong> J. Clin. Endocr. Metab. 86: 4529-4535, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549703">Vallette-Kasic et al. (2001)</a> found this mutation in homozygosity in 5 patients with combined pituitary hormone deficiency from 4 distinct families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549703" 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">rs121917841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917841;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=rs121917841" 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=rs121917841" 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=RCV000008568" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008568" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008568</a>
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<p><a href="#21" class="mim-tip-reference" title="Osorio, M. G. F., Kopp, P., Marui, S., Latronico, A. C., Mendonca, B. B., Arnhold, I. J. P. <strong>Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.</strong> J. Clin. Endocr. Metab. 85: 2779-2785, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946881</a>] [<a href="https://doi.org/10.1210/jcem.85.8.6744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10946881">Osorio et al. (2000)</a> studied a Brazilian girl, offspring of first cousins, who presented with short stature and combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>). Her cortisol response to hypoglycemia was determined at age 4.9, 10.7, and 14.1 years and remained normal. Magnetic resonance imaging at the age of 9 years revealed an anterior pituitary lobe of diminished height (3 mm; normal, 4.5 +/- 0.6), but radiography revealed a sella turcica volume above the normal mean. Sequencing of the PROP1 gene revealed homozygosity for a T-to-C transition at nucleotide 263 of the PROP1 gene, resulting in replacement of a highly conserved phenylalanine at codon 88 by serine (F88S). F88 constitutes the hydrophobic core of the first helix of the homeodomain of PROP1, and the substitution by the polar residue serine was expected to alter the secondary structure and impair binding of the mutated PROP1 to DNA target sequences. <a href="#21" class="mim-tip-reference" title="Osorio, M. G. F., Kopp, P., Marui, S., Latronico, A. C., Mendonca, B. B., Arnhold, I. J. P. <strong>Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.</strong> J. Clin. Endocr. Metab. 85: 2779-2785, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946881</a>] [<a href="https://doi.org/10.1210/jcem.85.8.6744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10946881">Osorio et al. (2000)</a> introduced the F88S mutation (which corresponds to murine F85S) into the murine Prop1 cDNA and assessed its consequences on DNA binding and trans-activation in vitro. In contrast to wildtype Prop1, the F88S mutant showed no significant DNA binding to a Prop1 response element in gel shift assays. Transcriptional activation of a luciferase reporter gene was reduced to approximately 34% compared with that of wildtype Prop1 in transiently transfected human embryonic kidney cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10946881" 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> rs587776682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776682;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/rs587776682?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=rs587776682" 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=rs587776682" 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=RCV000008569 OR RCV001385680" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008569, RCV001385680" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008569...</a>
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<p><a href="#1" class="mim-tip-reference" title="Agarwal, G., Bhatia, V., Cook, S., Thomas, P. Q. <strong>Adrenocorticotropin deficiency in combined pituitary hormone deficiency patients homozygous for a novel PROP1 deletion.</strong> J. Clin. Endocr. Metab. 85: 4556-4561, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134108</a>] [<a href="https://doi.org/10.1210/jcem.85.12.7013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11134108">Agarwal et al. (2000)</a> analyzed the PROP1 gene in a large consanguineous Indian pedigree with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>) and identified homozygosity for a 13-bp deletion in affected individuals, predicted to generate a null allele. Severe cortisol deficiency was observed in 2 patients in this family, suggesting a role for PROP1 in the differentiation and/or maintenance of corticotroph cells in the mature anterior pituitary. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11134108" 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 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587776683 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776683;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/rs587776683?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=rs587776683" 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=rs587776683" 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=RCV000008570 OR RCV001053115 OR RCV004584320" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008570, RCV001053115, RCV004584320" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008570...</a>
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<p>In 2 brothers with combined pituitary hormone deficiency involving GH, TSH, PRL, and gonadotropins (CPHD2; <a href="/entry/262600">262600</a>), who later also developed deficiencies of ACTH and cortisol secretion, <a href="#26" class="mim-tip-reference" title="Riepe, F. G., Partsch, C.-J., Blankenstein, O., Monig, H., Pfaffle, R. W., Sippell, W. G. <strong>Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.</strong> J. Clin. Endocr. Metab. 86: 4353-4357, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549674</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549674">Riepe et al. (2001)</a> identified compound heterozygosity for a 1-bp deletion (150delA) in the PROP1 gene and a 2-bp deletion (301delAG; <a href="#0002">601538.0002</a>). Both patients showed early pituitary enlargement by MRI, followed by subsequent marked hypoplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549674" 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> rs121917842 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917842;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/rs121917842?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=rs121917842" 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=rs121917842" 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=RCV000008571 OR RCV001383203" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008571, RCV001383203" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008571...</a>
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<p>In a French patient with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>), <a href="#30" class="mim-tip-reference" title="Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T. <strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong> J. Clin. Endocr. Metab. 86: 4529-4535, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549703">Vallette-Kasic et al. (2001)</a> found a novel mutation in PROP1, an arg73-to-his (R73H) substitution, resulting from a G-to-A transition at nucleotide 218 of the PROP1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549703" 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> rs121917843 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917843;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/rs121917843?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=rs121917843" 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=rs121917843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 brothers from a consanguineous Tunisian family with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>), <a href="#9" class="mim-tip-reference" title="Duquesnoy, P., Roy, A., Dastot, F., Ghali, I., Teinturier, C., Netchine, I., Cacheux, V., Hafez, M., Salah, N., Chaussain, J.-L., Goossens, M., Bougneres, P., Amselem, S. <strong>Human Prop-1: cloning, mapping, genomic structure: mutations in familial combined pituitary hormone deficiency.</strong> FEBS Lett. 437: 216-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9824293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9824293</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01234-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9824293">Duquesnoy et al. (1998)</a> identified a 217C-T transition in exon 2 of the PROP1 gene, resulting in an arg73-to-cys (R73C) substitution. The authors noted that arginine-73 is conserved in 95% of the more than 400 known homeodomain proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9824293" 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="#30" class="mim-tip-reference" title="Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T. <strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong> J. Clin. Endocr. Metab. 86: 4529-4535, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549703">Vallette-Kasic et al. (2001)</a> found the R73C mutation in homozygosity in 2 patients from 2 unrelated families, and in compound heterozygosity with R99X (<a href="#0011">601538.0011</a>) in 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549703" 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="#25" class="mim-tip-reference" title="Reynaud, R., Chadli-Chaieb, M., Vallette-Kasic, S., Barlier, A., Sarles, J., Pellegrini-Bouiller, I., Enjalbert, A., Chaieb, L., Brue, T. <strong>A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.</strong> J. Clin. Endocr. Metab. 89: 5779-5786, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531542</a>] [<a href="https://doi.org/10.1210/jc.2003-032124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531542">Reynaud et al. (2004)</a> found this mutation in homozygosity on all affected members of a large consanguineous Tunisian kindred. Transfection studies demonstrated that the mutant protein had 11.5% of the transactivation capacity of the wildtype protein. No detectable DNA binding was observed with R73C in electromobility shift assays, whereas in vitro translated PROP1 and R73C proteins were similar in their expression and electrophoretic properties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531542" 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> rs121917844 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917844;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/rs121917844?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=rs121917844" 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=rs121917844" 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=RCV000008573 OR RCV001203479" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008573, RCV001203479" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008573...</a>
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<p><a href="#30" class="mim-tip-reference" title="Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T. <strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong> J. Clin. Endocr. Metab. 86: 4529-4535, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549703">Vallette-Kasic et al. (2001)</a> found a C-to-T transition at nucleotide 295 of the PROP1 gene, resulting in substitution of arginine with a stop codon at codon 99 (R99X), in compound heterozygosity with R73C (<a href="#0010">601538.0010</a>) in 1 patient with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549703" 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>.0012 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137853100 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853100;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/rs137853100?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=rs137853100" 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=rs137853100" 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=RCV000008574 OR RCV000623197 OR RCV001851742 OR RCV003317030" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008574, RCV000623197, RCV001851742, RCV003317030" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008574...</a>
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<p>In 2 sibs, born to consanguineous parents, with combined pituitary hormone deficiency (CPHD2; <a href="/entry/262600">262600</a>) who presented with short stature, <a href="#31" class="mim-tip-reference" title="Vieira, T. C., Dias da Silva, M. R., Cerutti, J. M., Brunner, E., Borges, M., Arnaldi, L. T., Kopp, P., Abucham, J. <strong>Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of prophet of Pit-1 presenting as constitutional growth delay.</strong> J. Clin. Endocr. Metab. 88: 38-44, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519826</a>] [<a href="https://doi.org/10.1210/jc.2001-011872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519826">Vieira et al. (2003)</a> detected a novel homozygous transition 296G-A in exon 2 of the PROP1 gene that caused substitution of a highly conserved arginine by a glutamine at codon 99 (R99Q) in the second helix of the DNA-binding domain of the PROP1 protein. The index patient, a boy, was initially diagnosed with constitutional growth delay based on familial short stature, low parental target height, normal GH secretion, and imaging of the pituitary gland. On follow-up, auxologic data and pubertal delay prompted a thorough reevaluation, which documented GH, TSH, and gonadotropin deficiencies. Compared with wildtype PROP1, R99Q displays a significant decrease in DNA binding on a paired box response element (PRDQ9) and transactivation of a luciferase reporter gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12519826" 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>.0013 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917845 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917845;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=rs121917845" 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=rs121917845" 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=RCV000008575" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008575" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008575</a>
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<p>In 3 brothers from a consanguineous family of Tunisian descent with CPHD, who initially presented as cases of isolated hypogonadotropic hypogonadism (CPHD2; <a href="/entry/262600">262600</a>), <a href="#24" class="mim-tip-reference" title="Reynaud, R., Barlier, A., Vallette-Kasic, S., Saveanu, A., Guillet, M.-P., Simonin, G., Enjalbert, A., Valensi, P., Brue, T. <strong>An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.</strong> J. Clin. Endocr. Metab. 90: 4880-4887, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15941866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15941866</a>] [<a href="https://doi.org/10.1210/jc.2005-0119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15941866">Reynaud et al. (2005)</a> identified homozygosity for a 582G-A transition in the PROP1 gene, resulting in a trp194-to-ter (W194X) substitution that was predicted to truncate the protein in its transactivation domain. Transfection studies confirmed the deleterious effect of this mutation, whose transactivation capacity was only 34.4% that of wildtype. Unexpectedly altered DNA-binding properties suggested that the C-terminal end of the factor plays a role in protein-DNA interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15941866" 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>.0014 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008570 OR RCV001053115 OR RCV004584320" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008570, RCV001053115, RCV004584320" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008570...</a>
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<p>In 2 individuals with Hanhart dwarfism (CPHD2; <a href="/entry/262600">262600</a>) from the isolated community on the Island of Krk, <a href="#13" class="mim-tip-reference" title="Krzisnik, C., Kolacio, Z., Battelino, T., Brown, M., Parks, J. S., Laron, Z. <strong>The 'little people' of the Island of Krk - revisited: etiology of hypopituitarism revealed.</strong> J. Endocr. Genet. 1: 9-19, 1999."None>Krzisnik et al. (1999)</a> identified homozygosity for a 1-bp deletion (A) in codon 50 in exon 2 of the PROP1 gene, resulting in a frameshift and premature termination at codon 164. The predicted protein lacks all 3 alpha helices in the paired DNA-binding domain as well as the C-terminal transcriptional activation domain.</p>
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J. Clin. Endocr. Metab. 85: 4556-4561, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134108</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11134108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.85.12.7013" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.84.4.5630" target="_blank">Full Text</a>]
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Nasonkin, I. O., Ward, R. D., Raetzman, L. T., Seasholtz, A. F., Saunders, T. L., Gillespie, P. J., Camper, S. A.
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<strong>Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459176</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459176" 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/ddh311" target="_blank">Full Text</a>]
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Osorio, M. G. F., Kopp, P., Marui, S., Latronico, A. C., Mendonca, B. B., Arnhold, I. J. P.
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<strong>Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946881</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10946881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.85.8.6744" target="_blank">Full Text</a>]
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Osorio, M. G. F., Marui, S., Jorge, A. A. L., Latronico, A. C., Lo, L. S. S., Leite, C. C., Estefan, V., Mendonca, B. B., Arnhold, I. J. P.
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<strong>Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414875</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12414875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2001-011936" target="_blank">Full Text</a>]
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Pernasetti, F., Toledo, S. P. A., Vasilyev, V. V., Hayashida, C. Y., Cogan, J. D., Ferrari, C., Lourenco, D. M., Mellon, P. L.
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<strong>Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene.</strong>
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J. Clin. Endocr. Metab. 85: 390-397, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10634415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10634415</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10634415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.85.1.6324" target="_blank">Full Text</a>]
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Reynaud, R., Barlier, A., Vallette-Kasic, S., Saveanu, A., Guillet, M.-P., Simonin, G., Enjalbert, A., Valensi, P., Brue, T.
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<strong>An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.</strong>
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J. Clin. Endocr. Metab. 90: 4880-4887, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15941866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15941866</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15941866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2005-0119" target="_blank">Full Text</a>]
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Reynaud, R., Chadli-Chaieb, M., Vallette-Kasic, S., Barlier, A., Sarles, J., Pellegrini-Bouiller, I., Enjalbert, A., Chaieb, L., Brue, T.
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<strong>A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.</strong>
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J. Clin. Endocr. Metab. 89: 5779-5786, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2003-032124" target="_blank">Full Text</a>]
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Riepe, F. G., Partsch, C.-J., Blankenstein, O., Monig, H., Pfaffle, R. W., Sippell, W. G.
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<strong>Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.</strong>
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J. Clin. Endocr. Metab. 86: 4353-4357, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549674</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.86.9.7828" target="_blank">Full Text</a>]
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Rosenbloom, A. L., Almonte, A. S., Brown, M. R., Fisher, D. A., Baumbach, L., Parks, J. S.
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<strong>Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.</strong>
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J. Clin. Endocr. Metab. 84: 50-57, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920061</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.84.1.5366" target="_blank">Full Text</a>]
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Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S., Norman, D. J., O'Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P., Zuo, L., Gleiberman, A. S., Andersen, B., Beamer, W. G., Rosenfeld, M. G.
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<strong>Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.</strong>
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Nature 384: 327-333, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8934515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8934515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8934515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/384327a0" target="_blank">Full Text</a>]
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Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.86.9.7811" target="_blank">Full Text</a>]
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Vieira, T. C., Dias da Silva, M. R., Cerutti, J. M., Brunner, E., Borges, M., Arnaldi, L. T., Kopp, P., Abucham, J.
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<strong>Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of prophet of Pit-1 presenting as constitutional growth delay.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519826</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12519826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2001-011872" target="_blank">Full Text</a>]
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Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G.
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<strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong>
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Nature Genet. 18: 147-149, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462743</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0298-147" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Carol A. Bocchini - updated : 05/23/2020
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Marla J. F. O'Neill - updated : 10/2/2009<br>George E. Tiller - updated : 5/22/2007<br>John A. Phillips, III - updated : 5/11/2006<br>John A. Phillips, III - updated : 4/7/2006<br>John A. Phillips, III - updated : 4/6/2006<br>Victor A. McKusick - updated : 12/5/2005<br>John A. Phillips, III - updated : 7/21/2005<br>John A. Phillips, III - updated : 6/29/2005<br>John A. Phillips, III - updated : 4/8/2005<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 3/22/2002<br>John A. Phillips, III - updated : 3/21/2002<br>Ada Hamosh - updated : 11/26/2001<br>George E. Tiller - updated : 10/15/2001<br>John A. Phillips, III - updated : 10/10/2001<br>John A. Phillips, III - updated : 3/7/2001<br>John A. Phillips, III - updated : 3/20/2000<br>John A. Phillips, III - updated : 10/14/1999<br>John A. Phillips, III - updated : 9/20/1999<br>John A. Phillips, III - revised : 9/3/1999<br>John A. Phillips, III - reorganized : 9/3/1999<br>John A. Phillips, III - updated : 3/19/1999<br>John A. Phillips, III - updated : 3/3/1999<br>John A. Phillips, III - updated : 2/9/1999<br>Victor A. McKusick - updated : 1/28/1998<br>Victor A. McKusick - updated : 1/23/1998<br>John A. Phillips, III - updated : 1/8/1997
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Victor A. McKusick : 11/27/1996
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carol : 05/23/2020
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carol : 01/28/2020<br>carol : 07/14/2016<br>carol : 7/9/2016<br>alopez : 4/27/2015<br>mcolton : 4/21/2015<br>carol : 5/21/2014<br>mcolton : 5/16/2014<br>carol : 5/13/2014<br>carol : 12/30/2013<br>terry : 5/11/2010<br>carol : 10/2/2009<br>alopez : 6/2/2009<br>terry : 12/17/2007<br>wwang : 5/30/2007<br>terry : 5/22/2007<br>alopez : 5/11/2006<br>alopez : 4/7/2006<br>alopez : 4/6/2006<br>alopez : 1/6/2006<br>alopez : 1/6/2006<br>terry : 12/5/2005<br>terry : 10/12/2005<br>terry : 8/3/2005<br>alopez : 7/21/2005<br>alopez : 6/29/2005<br>alopez : 4/8/2005<br>terry : 3/18/2004<br>alopez : 3/17/2004<br>tkritzer : 4/22/2003<br>tkritzer : 4/21/2003<br>terry : 4/8/2003<br>alopez : 3/22/2002<br>alopez : 3/21/2002<br>alopez : 11/26/2001<br>terry : 11/26/2001<br>cwells : 10/30/2001<br>cwells : 10/15/2001<br>alopez : 10/10/2001<br>carol : 9/10/2001<br>alopez : 3/8/2001<br>alopez : 3/7/2001<br>mgross : 3/27/2000<br>terry : 3/20/2000<br>alopez : 10/14/1999<br>alopez : 10/14/1999<br>mgross : 9/20/1999<br>carol : 9/13/1999<br>carol : 9/3/1999<br>carol : 9/3/1999<br>mgross : 3/24/1999<br>mgross : 3/19/1999<br>mgross : 3/11/1999<br>mgross : 3/3/1999<br>mgross : 2/9/1999<br>terry : 6/3/1998<br>carol : 3/21/1998<br>mark : 3/6/1998<br>mark : 1/28/1998<br>terry : 1/28/1998<br>mark : 1/27/1998<br>terry : 1/23/1998<br>jenny : 5/27/1997<br>jenny : 5/27/1997<br>mark : 12/12/1996<br>terry : 12/10/1996<br>jenny : 12/6/1996<br>mark : 11/27/1996<br>mark : 11/27/1996
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<strong>*</strong> 601538
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PROP PAIRED-LIKE HOMEOBOX 1; PROP1
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<em>Alternative titles; symbols</em>
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PROPHET OF PIT1, PAIRED-LIKE HOMEODOMAIN TRANSCRIPTION FACTOR
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<strong><em>HGNC Approved Gene Symbol: PROP1</em></strong>
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Cytogenetic location: 5q35.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:177,992,235-177,996,242 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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5q35.3
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Pituitary hormone deficiency, combined, 2
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<span class="mim-font">
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262600
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>PROP1 is a pituitary-specific paired-like homeodomain transcription factor that plays a crucial role in the proper development of somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs (summary by Duquesnoy et al., 1998). </p>
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<strong>Cloning and Expression</strong>
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<p>Duquesnoy et al. (1998) cloned a human PROP1 cDNA, which encodes a deduced 226-amino acid protein that shares 73% overall sequence identity with mouse Prop1. </p><p>PROP1 mRNA is expressed in the developing pituitary gland before PIT1 mRNA expression and maximum expression are observed at e12.0. After e14.5, PROP1 mRNA expression rapidly decreases, and only trace amounts of mRNA are detectable in adult mouse pituitary (Sornson et al., 1996). Nakamura et al. (1999) studied human PROP1 expression in adult pituitary and pituitary adenomas. Human PROP1 transcripts were detected in normal adult pituitary by Northern blot analysis, and in all pituitary adenomas examined by RT-PCR analysis. </p>
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<strong>Gene Structure</strong>
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<p>Duquesnoy et al. (1998) determined that the PROP1 gene has at least 3 exons and spans less than 4 kb of genomic DNA. </p>
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<strong>Mapping</strong>
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<p>There is considerable homology of synteny between mouse chromosome 11 and human 5q; the linkage of the df (Prop1) gene to the interleukin cluster (e.g., IL3, 147740) on chromosome 11 in the mouse suggested that the human PROP1 gene is located on human chromosome 5q. Rosenfeld and Wu (1998) confirmed that PROP1 is located on 5q by radiation hybrid mapping.</p><p>By fluorescence in situ hybridization, Duquesnoy et al. (1998) mapped the PROP1 gene to chromosome 5q35. </p>
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<strong>Molecular Genetics</strong>
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<p>Inactivating mutations in PROP1 perturb ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes. These developmental defects result in deficiencies of luteinizing hormone (LH; 152780), follicle-stimulating hormone (FSH; 136530), growth hormone (GH; 139250), prolactin (PRL; 176760), and thyroid-stimulating hormone (TSH; 188540).</p><p>Wu et al. (1998) identified 4 families in which combined pituitary hormone deficiency (CPHD2; 262600) was produced by homozygosity or compound heterozygosity for inactivating mutations of the PROP1 gene. These mutations in the PROP1 gene resulted in a gene product with reduced DNA binding and transcriptional activation ability in comparison to the product of the murine df mutation (e.g., 601538.0002). In contrast to individuals with mutations in the human homolog of the mouse Pit1 gene, POU1F1 (173110), those with PROP1 mutations cannot produce luteinizing hormone or follicle-stimulating hormone at a sufficient level and do not enter puberty spontaneously. The results identified a major cause of combined pituitary hormone deficiency in humans and suggested a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes, and caudomedial thyrotropes. </p><p>In 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, Fluck et al. (1998) identified homozygosity for the R120C mutation in the PROP1 gene (601538.0001). </p><p>Whereas a variety of PROP1 mutations have been reported, Cogan et al. (1998) found by analysis of 10 independent CPHD kindreds that the 301delAG allele (601538.0002) constitutes a major portion, perhaps 55%, of PROP1 mutant alleles. Cogan et al. (1998) also concluded from analysis of a tightly linked polymorphic marker that the 301delAG allele may be a recurring mutation. </p><p>In 2 individuals with CPHD2 (Hanhart dwarfism) from the isolated community on the Island of Krk in the Adriatic Sea, Krzisnik et al. (1999) identified homozygosity for a frameshift mutation in the PROP1 gene (601538.0014).</p><p>Nakamura et al. (1999) sequenced PROP1 cDNAs from pituitary adenomas. They found that the amino acid sequence of cloned human PROP1 cDNA was identical to the reported sequence, except for an ala142-to-thr substitution. They concluded that this substitution is a polymorphism because it did not alter transcriptional activity, and 7 of 28 (25%) alleles encoded ala. Because sequence analysis of PROP1 cDNAs from human pituitary adenomas only revealed 5 silent nucleic acid substitutions, Nakamura et al. (1999) concluded that PROP1 mutations do not represent a frequent mechanism of human pituitary tumorigenesis. </p><p>Deladoey et al. (1999) screened families and patients suffering from different forms of CPHD for PROP1 gene alterations to define possible hotspots and the frequency of the different gene alterations found. Of 73 subjects (36 families) analyzed, they identified 35 patients, belonging to 18 unrelated families, with CPHD caused by a PROP1 gene defect. The PROP1 gene alterations included 3 missense mutations, 2 frameshift mutations, and 1 splice site mutation. The 2 reported frameshift mutations could be caused by any 2-bp GA or AG deletion at either the 148-GGA-GGG-153 or 295-CGA-GAG-AGT-303 position. As any combination of a GA or AG deletion yields the same sequencing data, the authors called the frameshift mutations 149delGA and 296delGA, respectively. All but 1 mutation were located in the homeodomain of the PROP1 gene. Deladoey et al. (1999) concluded that 3 tandem repeats of the dinucleotides GA at location 296 to 302 in the PROP1 gene represent a hotspot for CPHD. </p><p>Vallette-Kasic et al. (2001) screened the PROP1 gene in 23 CPHD patients and identified homozygosity or compound heterozygosity for 4 mutations in 9 patients from 8 unrelated families. All mutations were located in exon 2 and affected only 2 different sites (see 601538.0005 and 601538.0009-601538.0011). Vallette-Kasic et al. (2001) stated that, in keeping with previous reports, they found no correlation between phenotype and genotype. </p><p>Reynaud et al. (2004) reported a homozygous R73C mutation of PROP1 (601538.0010) in all 10 patients studied from a large consanguineous Tunisian kindred with CPHD; heterozygosity for the mutation was found in 6 unaffected parents or sibs. </p><p>In a retrospective longitudinal analysis of 9 CPHD patients with known PROP1 mutations, primarily involving homozygous or compound heterozygous deletions (e.g., 601538.0002 and 601538.0008), Bottner et al. (2004) found that all patients developed at least partial adrenal insufficiency requiring hydrocortisone therapy. The authors concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence. </p><p>In 3 brothers from a consanguineous family of Tunisian descent with CPHD, who initially presented as cases of isolated hypogonadotropic hypogonadism, Reynaud et al. (2005) identified homozygosity for a nonsense mutation in the PROP1 gene (W194X; 601538.0013). </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Osorio et al. (2002) stated that the pathogenesis of pituitary stalk interruption and ectopic posterior lobe, frequently observed on MRI in patients with GH deficiency (see 262400), was controversial. They performed pituitary stimulation tests and MRI, and studied the PROP1, GH1, and GHRHR (139191) genes, in 76 patients with GHD. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequencies of consanguinity (P less than 0.001) and familial cases (P less than 0.05) and lower frequency of breech delivery or hypoxemia at birth (P less than 0.005). On MRI, all patients with mutations had an intact pituitary stalk, whereas it was interrupted or thin in 74% without mutations (P less than 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations versus 13% without mutations (P less than 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP1 and PIT1 mutations and suggestive of hypothalamic origin in 81% without mutations. PROP1, GH1, and GHRHR mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. Osorio et al. (2002) concluded that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiologic diagnosis of GHD. </p>
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<strong>Animal Model</strong>
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<p>The Snell dwarf mouse (dw) has a mutation in the Pit1 gene (POU1F1; 173110) which encodes pituitary-specific transcription factor-1. Mutations in the human homolog, PIT1, are the basis of combined pituitary hormone deficiency in humans (e.g., 173110.0001). Reasoning that the Snell dwarf might represent a point mutation, Li et al. (1990) did studies which demonstrated a G-to-T change that converted the tryptophan residue in the POU-homeodomain (trp261) to cysteine. Neither mRNA nor protein was detected in either of the 2 types of dwarf mice. They also demonstrated that the Ames dwarf mouse (df) has a nonallelic mutation that maps to mouse chromosome 11 and is associated with absence of detectable Pit1 gene expression. Thus, the Ames mutation df appeared to be epistatic to the Pit1 locus. The df locus may be involved in the regulation of Pit1, or perhaps in conjunction with Pit1, in the specification and/or maintenance of the 3 specific pituitary cell types affected by the mutation. Andersen et al. (1995) pointed out that the Ames dwarf exhibits a phenotype identical to that of the Pit1-mutated mice. Their studies indicated that initial activation of the Pit1 gene is deficient in the Ames dwarf. This suggested that the df gene is required for activation of the Pit1 gene. </p><p>Sornson et al. (1996) isolated the murine gene that is mutant in the Ames dwarf (df) by positional cloning and identified a tissue-specific, 'paired'-like homeodomain transcription factor, which they termed 'Prophet of Pit1' (Prop1). The df phenotype resulted from an apparent failure of initial determination of the Pit1 lineage required for production of growth hormone, prolactin, or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit1 gene expression. The results suggested to Sornson et al. (1996) that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis. </p><p>Analysis of double heterozygotes and double mutants by Gage et al. (1996) indicated that the df and dw genes act sequentially in the same genetic pathway. Double heterozygotes had no reduction in growth rate or final adult size. Double homozygotes had essentially the same phenotype as the single mutants and were recovered at the predicted frequency, indicating that there are no previously unrecognized, redundant functions of the 2 genes. The df mutants failed to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands was reduced by e14.5, while Pit1dw mutants downregulate Rpx appropriately and exhibit normal cell proliferation up to e14.5. These occurrences suggest that df acts earlier in the differentiation pathway than Pit1 to regulate pituitary ontogeny. </p><p>Brown-Borg et al. (1996) noted that Ames dwarf mice (df/df) are of normal body size at birth but postnatal growth is severely retarded and the body size of adult animals is approximately one-third of normal. The authors found, however, that df/df mice lived much longer than normal mice, with a difference in average life span being more than 350 days for males and more than 470 days for females. Two df/df females reached the remarkable age of 4 years. These findings were particularly striking because Ames dwarfs exhibit some characteristics of reduced immune function and the animals were maintained in a conventional environment and fed lab chow and tap water without restriction. Brown-Borg et al. (1996) speculated on the mechanism of the increased survival. </p><p>Cushman et al. (2001) generated transgenic mice which constitutively expressed Prop1. The terminal differentiation of pituitary gonadotropes was delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurred normally, but thyrotrope function was impaired, resulting in mild hypothyroidism. Aged mice exhibited defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke cleft cysts and tumors. The authors concluded that silencing Prop1 is important for normal pituitary development and function, and that gain-of-function mutations in PROP1 could contribute to common human pituitary endocrinopathies and tumors. </p><p>By reducing the number of calories consumed by Ames dwarf mice, Bartke et al. (2001) investigated whether the longevity associated with Ames dwarf mice is influenced by similar or independent mechanisms to the longevity associated with caloric restrictions. Bartke et al. (2001) found that 70% caloric restriction conferred a further life span increase in the dwarf, indicating that the 2 factors may act through different pathways. Survival plots indicated that although both dwarfism and calorie restriction extend longevity, the effect of reduced food intake is associated primarily with a change in the slope of the survival curve (i.e., it reduces the rate of age-related mortality), whereas the effect of dwarfism mainly reflects a shift in the age at which the age-dependent increase in mortality risk first becomes appreciable. Calorie restriction, therefore, seems to decelerate aging, whereas the Prop1(df) allele seems to delay it. </p><p>Nasonkin et al. (2004) showed that deletion of Prop1 in mice caused severe pituitary hypoplasia with failure of the entire Pit1 lineage and delayed gonadotrope development. Pituitary hormone deficiencies caused secondary endocrine problems and a high rate of perinatal mortality due to respiratory distress. Lung atelectasis in mutants correlated with reduced levels of NKX2.1 (TITF1; 600635) and surfactant (SFTPA1; 178630). Lethality of mice homozygous for either the null allele or a spontaneous hypomorphic allele was strongly influenced by genetic background. </p>
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<strong>History</strong>
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<span class="mim-text-font">
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<p>The mouse gene Prop1, which is mutant in the Ames dwarf (df), was isolated by Sornson et al. (1996). The first humans with CPHD due to PROP1 defects were reported by Wu et al. (1998). The human PROP1 mutations resulted in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the Ames dwarf mutation (e.g., 601538.0002). </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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<strong>14 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PROP1, ARG120CYS
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<br />
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SNP: rs121917839,
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|
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gnomAD: rs121917839,
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|
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ClinVar: RCV000008563, RCV001389806
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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">
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|
<p>In a family with 2 brothers and a sister with combined pituitary hormone deficiency (CPHD2; 262600), Wu et al. (1998) identified a C-to-T transition resulting in an arg120-to-cys amino acid substitution. </p><p>In 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, Fluck et al. (1998) identified homozygosity for the R120C mutation in the PROP1 gene. The authors noted that there was variability in the phenotype, even among these patients with the same mutation. </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>.0002 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
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</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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PROP1, 2-BP DEL, 301AG
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<br />
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SNP: rs193922688,
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gnomAD: rs193922688,
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|
|
|
ClinVar: RCV000008566, RCV000030379, RCV000517269, RCV002254517, RCV004755724
|
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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 each of 2 separate families, Wu et al. (1998) showed that 3 sibs with combined pituitary hormone deficiency (CPHD2; 262600) carried a 2-bp deletion (301A and 302G) leading to a frameshift in the coding sequence starting at codon 101 and premature termination at codon 109. The truncation resulted in the loss of the DNA-binding homeodomain and the C-terminal transactivation domain of PROP1. </p><p>Cogan et al. (1998) determined the frequency of the 301delAG mutation in exon 2 of PROP1 in 10 independently ascertained combined pituitary hormone deficiency (CPHD) kindreds and 21 sporadic cases of CPHD from 8 different countries. They found that 55% (11 of 20) of the PROP1 alleles were 301delAG in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles in the 21 sporadic cases were 301delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given thyrotropin-releasing hormone stimulation tests) was 50% (3 of 6) in the CPHD cases with pituitary defects, and 0% (0 of 34) in the CPHD cases with hypothalamic defects. Using whole genome radiation hybrid analysis, they localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. The authors concluded that analysis of this marker in affected subjects with the 301delAG mutation suggests that rather than being inherited from a common founder, 301delAG may be a recurring mutation. </p><p>In 2 unrelated females with CPHD, Mendonca et al. (1999) identified homozygosity for the 301AG deletion in the PROP1 gene. MRI findings changed over time in these patients, and 1 had partial cortisol deficiency. The authors concluded that a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced T1 signal on MRI suggests PROP1 deficiency; that pituitary morphology can change during follow-up of patients with PROP1 mutations; and that hormonal deficiencies associated with PROP1 mutations can include the adrenal axis. </p><p>In 10 CPHD patients from a large Brazilian kindred, 9 of whom were born of consanguineous marriages, Pernasetti et al. (2000) identified homozygosity for the 301AG deletion in PROP1. The authors observed ACTH/cortisol insufficiency in 5 of 6 of the older patients and in one 11-year-old patient, and suggested that the phenotype of this mutation includes late-onset adrenal insufficiency. </p><p>Riepe et al. (2001) found this mutation in compound heterozygosity with 150delA (601538.0008) in 2 brothers with typical manifestations of PROP1 deficiency. </p><p>The 301-302delAG frameshift mutation was found in homozygous state as the cause of the CPHD in the Hutterite cases reported by McKusick and Rimoin (1967) (Mosely et al., 2002). </p><p>In 3 adult sibs, aged 18 to 25 years, with short stature, hypothyroidism, and lack of pubertal maturation, Lee et al. (2004) identified homozygosity for the 301AG deletion in PROP1. All 3 patients responded with a dramatic increase in linear growth to treatment with GH and thyroid replacement administered prior to beginning sex steroid replacement therapy. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
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PROP1, PHE117ILE
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<br />
|
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|
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SNP: rs121917840,
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|
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|
|
|
gnomAD: rs121917840,
|
|
|
|
|
|
ClinVar: RCV000008564, RCV001053358
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of combined pituitary hormone deficiency (CPHD2; 262600), Wu et al. (1998) identified compound heterozygosity for mutations in the PROP1 gene. A 2-bp deletion (301delAG; 601538.0002) was inherited from the mother; the paternal allele carried a T-to-A transversion at nucleotide 349, resulting in a phe117-to-ile amino acid substitution. Magnetic resonance imaging revealed hypocellular pituitary in this patient. This patient and the affected individuals homozygous for the 301delAG deletion failed to respond to growth hormone-releasing hormone (GHRH; 139190), thyrotropin-releasing hormone (TRH; 613879), and LH-releasing hormone (LHRH; 152760) stimulation. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, 2-BP DEL, 149GA
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776681,
|
|
|
|
|
|
|
|
ClinVar: RCV000008565
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 Russian children with combined pituitary hormone deficiency (CPHD2; 262600), including a brother and sister and 3 unrelated children, Fofanova et al. (1998) identified compound heterozygosity for 2 2-bp deletions in the PROP1 gene, 149delGA and 296delGA (601538.0005), both of which result in premature termination of the protein due to a stop codon at residue 109. Another affected brother and sister and an unrelated girl with CPHD were homozygous for 149delGA. All parents were of normal stature and each was heterozygous for a wildtype allele and 1 of the deletions, respectively. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, 2-BP DEL, 296GA
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000008566, RCV000030379, RCV000517269, RCV002254517, RCV004755724
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 2-bp deletion in the PROP1 gene (296delGA) that was found in compound heterozygous state in patients with combined pituitary hormone deficiency (CPHD2; 262600) by Fofanova et al. (1998), see 601538.0004. </p><p>In 8 patients from a large Dominican kindred with CPHD2, the largest such family reported to that time, Rosenbloom et al. (1999) identified homozygosity for the 296delGA mutation in the PROP1 gene. </p><p>Deladoey et al. (1999) found this mutation in patients from distinct genetic backgrounds and described the site of the mutation as one of high mutability. </p><p>Vallette-Kasic et al. (2001) found this mutation in homozygosity in 5 patients with combined pituitary hormone deficiency from 4 distinct families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, PHE88SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917841,
|
|
|
|
|
|
|
|
ClinVar: RCV000008568
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Osorio et al. (2000) studied a Brazilian girl, offspring of first cousins, who presented with short stature and combined pituitary hormone deficiency (CPHD2; 262600). Her cortisol response to hypoglycemia was determined at age 4.9, 10.7, and 14.1 years and remained normal. Magnetic resonance imaging at the age of 9 years revealed an anterior pituitary lobe of diminished height (3 mm; normal, 4.5 +/- 0.6), but radiography revealed a sella turcica volume above the normal mean. Sequencing of the PROP1 gene revealed homozygosity for a T-to-C transition at nucleotide 263 of the PROP1 gene, resulting in replacement of a highly conserved phenylalanine at codon 88 by serine (F88S). F88 constitutes the hydrophobic core of the first helix of the homeodomain of PROP1, and the substitution by the polar residue serine was expected to alter the secondary structure and impair binding of the mutated PROP1 to DNA target sequences. Osorio et al. (2000) introduced the F88S mutation (which corresponds to murine F85S) into the murine Prop1 cDNA and assessed its consequences on DNA binding and trans-activation in vitro. In contrast to wildtype Prop1, the F88S mutant showed no significant DNA binding to a Prop1 response element in gel shift assays. Transcriptional activation of a luciferase reporter gene was reduced to approximately 34% compared with that of wildtype Prop1 in transiently transfected human embryonic kidney cells. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, 13-BP DEL, NT112
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776682,
|
|
|
|
|
|
gnomAD: rs587776682,
|
|
|
|
|
|
ClinVar: RCV000008569, RCV001385680
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Agarwal et al. (2000) analyzed the PROP1 gene in a large consanguineous Indian pedigree with combined pituitary hormone deficiency (CPHD2; 262600) and identified homozygosity for a 13-bp deletion in affected individuals, predicted to generate a null allele. Severe cortisol deficiency was observed in 2 patients in this family, suggesting a role for PROP1 in the differentiation and/or maintenance of corticotroph cells in the mature anterior pituitary. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, 1-BP DEL, 150A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776683,
|
|
|
|
|
|
gnomAD: rs587776683,
|
|
|
|
|
|
ClinVar: RCV000008570, RCV001053115, RCV004584320
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with combined pituitary hormone deficiency involving GH, TSH, PRL, and gonadotropins (CPHD2; 262600), who later also developed deficiencies of ACTH and cortisol secretion, Riepe et al. (2001) identified compound heterozygosity for a 1-bp deletion (150delA) in the PROP1 gene and a 2-bp deletion (301delAG; 601538.0002). Both patients showed early pituitary enlargement by MRI, followed by subsequent marked hypoplasia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, ARG73HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917842,
|
|
|
|
|
|
gnomAD: rs121917842,
|
|
|
|
|
|
ClinVar: RCV000008571, RCV001383203
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with combined pituitary hormone deficiency (CPHD2; 262600), Vallette-Kasic et al. (2001) found a novel mutation in PROP1, an arg73-to-his (R73H) substitution, resulting from a G-to-A transition at nucleotide 218 of the PROP1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, ARG73CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917843,
|
|
|
|
|
|
gnomAD: rs121917843,
|
|
|
|
|
|
ClinVar: RCV000008572, RCV000821200
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers from a consanguineous Tunisian family with combined pituitary hormone deficiency (CPHD2; 262600), Duquesnoy et al. (1998) identified a 217C-T transition in exon 2 of the PROP1 gene, resulting in an arg73-to-cys (R73C) substitution. The authors noted that arginine-73 is conserved in 95% of the more than 400 known homeodomain proteins. </p><p>Vallette-Kasic et al. (2001) found the R73C mutation in homozygosity in 2 patients from 2 unrelated families, and in compound heterozygosity with R99X (601538.0011) in 1 patient. </p><p>Reynaud et al. (2004) found this mutation in homozygosity on all affected members of a large consanguineous Tunisian kindred. Transfection studies demonstrated that the mutant protein had 11.5% of the transactivation capacity of the wildtype protein. No detectable DNA binding was observed with R73C in electromobility shift assays, whereas in vitro translated PROP1 and R73C proteins were similar in their expression and electrophoretic properties. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, ARG99TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917844,
|
|
|
|
|
|
gnomAD: rs121917844,
|
|
|
|
|
|
ClinVar: RCV000008573, RCV001203479
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Vallette-Kasic et al. (2001) found a C-to-T transition at nucleotide 295 of the PROP1 gene, resulting in substitution of arginine with a stop codon at codon 99 (R99X), in compound heterozygosity with R73C (601538.0010) in 1 patient with combined pituitary hormone deficiency (CPHD2; 262600). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PROP1, ARG99GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853100,
|
|
|
|
|
|
gnomAD: rs137853100,
|
|
|
|
|
|
ClinVar: RCV000008574, RCV000623197, RCV001851742, RCV003317030
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
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<p>In 2 sibs, born to consanguineous parents, with combined pituitary hormone deficiency (CPHD2; 262600) who presented with short stature, Vieira et al. (2003) detected a novel homozygous transition 296G-A in exon 2 of the PROP1 gene that caused substitution of a highly conserved arginine by a glutamine at codon 99 (R99Q) in the second helix of the DNA-binding domain of the PROP1 protein. The index patient, a boy, was initially diagnosed with constitutional growth delay based on familial short stature, low parental target height, normal GH secretion, and imaging of the pituitary gland. On follow-up, auxologic data and pubertal delay prompted a thorough reevaluation, which documented GH, TSH, and gonadotropin deficiencies. Compared with wildtype PROP1, R99Q displays a significant decrease in DNA binding on a paired box response element (PRDQ9) and transactivation of a luciferase reporter gene. </p>
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</span>
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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>.0013 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PROP1, TRP194TER
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<br />
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SNP: rs121917845,
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ClinVar: RCV000008575
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</span>
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<span class="mim-text-font">
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<p>In 3 brothers from a consanguineous family of Tunisian descent with CPHD, who initially presented as cases of isolated hypogonadotropic hypogonadism (CPHD2; 262600), Reynaud et al. (2005) identified homozygosity for a 582G-A transition in the PROP1 gene, resulting in a trp194-to-ter (W194X) substitution that was predicted to truncate the protein in its transactivation domain. Transfection studies confirmed the deleterious effect of this mutation, whose transactivation capacity was only 34.4% that of wildtype. Unexpectedly altered DNA-binding properties suggested that the C-terminal end of the factor plays a role in protein-DNA interaction. </p>
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</span>
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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>.0014 PITUITARY HORMONE DEFICIENCY, COMBINED, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PROP1, 1-BP DEL, CODON 50, EX2
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<br />
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ClinVar: RCV000008570, RCV001053115, RCV004584320
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 individuals with Hanhart dwarfism (CPHD2; 262600) from the isolated community on the Island of Krk, Krzisnik et al. (1999) identified homozygosity for a 1-bp deletion (A) in codon 50 in exon 2 of the PROP1 gene, resulting in a frameshift and premature termination at codon 164. The predicted protein lacks all 3 alpha helices in the paired DNA-binding domain as well as the C-terminal transcriptional activation domain.</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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Cogan, J. D., Wu, W., Phillips, J. A., III, Arnhold, I. J. P., Agapito, A., Fofanova, O. V., Osorio, M. G. F., Bircan, I., Moreno, A., Mendonca, B. B.
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<strong>The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency.</strong>
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Cushman, L. J., Watkins-Chow, D. E., Brinkmeier, M. L., Raetzman, L. T., Radak, A. L., Lloyd, R. V., Camper, S. A.
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<strong>Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility.</strong>
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Deladoey, J., Fluck, C., Buyukgebiz, A., Kuhlmann, B. V., Eble, A., Hindmarsh, P. C., Wu, W., Mullis, P. E.
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Duquesnoy, P., Roy, A., Dastot, F., Ghali, I., Teinturier, C., Netchine, I., Cacheux, V., Hafez, M., Salah, N., Chaussain, J.-L., Goossens, M., Bougneres, P., Amselem, S.
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Fluck, C., Deladoey, J., Rutishauser, K., Eble, A., Marti, U., Wu, W., Mullis, P. E.
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<strong>Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of arg to cys at codon 120 (R120C).</strong>
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[Full Text: https://doi.org/10.1210/jcem.83.10.5172]
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Fofanova, O., Takamura, N., Kinoshita, E., Parks, J. S., Brown, M. R., Peterkova, V. A., Evgrafov, O. V., Goncharov, N. P., Bulatov, A. A., Dedov, I. I., Yamashita, S.
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J. Clin. Endocr. Metab. 83: 2601-2604, 1998.
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[PubMed: 9661653]
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Gage, P. J., Brinkmeier, M. L., Scarlett, L. M., Knapp, L. T., Camper, S. A., Mahon, K. A.
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<strong>Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.</strong>
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Osorio, M. G. F., Marui, S., Jorge, A. A. L., Latronico, A. C., Lo, L. S. S., Leite, C. C., Estefan, V., Mendonca, B. B., Arnhold, I. J. P.
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<p class="mim-text-font">
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Pernasetti, F., Toledo, S. P. A., Vasilyev, V. V., Hayashida, C. Y., Cogan, J. D., Ferrari, C., Lourenco, D. M., Mellon, P. L.
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<strong>Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene.</strong>
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[PubMed: 10634415]
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<p class="mim-text-font">
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Reynaud, R., Barlier, A., Vallette-Kasic, S., Saveanu, A., Guillet, M.-P., Simonin, G., Enjalbert, A., Valensi, P., Brue, T.
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<strong>An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.</strong>
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[PubMed: 15941866]
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</p>
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<li>
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<p class="mim-text-font">
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Reynaud, R., Chadli-Chaieb, M., Vallette-Kasic, S., Barlier, A., Sarles, J., Pellegrini-Bouiller, I., Enjalbert, A., Chaieb, L., Brue, T.
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<strong>A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.</strong>
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[PubMed: 15531542]
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[Full Text: https://doi.org/10.1210/jc.2003-032124]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Riepe, F. G., Partsch, C.-J., Blankenstein, O., Monig, H., Pfaffle, R. W., Sippell, W. G.
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<strong>Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.</strong>
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[Full Text: https://doi.org/10.1210/jcem.86.9.7828]
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<p class="mim-text-font">
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Rosenbloom, A. L., Almonte, A. S., Brown, M. R., Fisher, D. A., Baumbach, L., Parks, J. S.
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<strong>Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.</strong>
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[PubMed: 9920061]
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[Full Text: https://doi.org/10.1210/jcem.84.1.5366]
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Rosenfeld, M. G., Wu, W.
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<strong>Personal Communication.</strong>
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San Diego, Calif. 1/23/1998.
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</li>
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Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S., Norman, D. J., O'Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P., Zuo, L., Gleiberman, A. S., Andersen, B., Beamer, W. G., Rosenfeld, M. G.
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<strong>Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.</strong>
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Nature 384: 327-333, 1996.
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[PubMed: 8934515]
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[Full Text: https://doi.org/10.1038/384327a0]
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Vallette-Kasic, S., Barlier, A., Teinturier, C., Diaz, A., Manavela, M., Berthezene, F., Bouchard, P., Chaussain, J. L., Brauner, R., Pellegrini-Bouiller, I., Jaquet, P., Enjalbert, A., Brue, T.
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<strong>PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.</strong>
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J. Clin. Endocr. Metab. 86: 4529-4535, 2001.
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[PubMed: 11549703]
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[Full Text: https://doi.org/10.1210/jcem.86.9.7811]
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Vieira, T. C., Dias da Silva, M. R., Cerutti, J. M., Brunner, E., Borges, M., Arnaldi, L. T., Kopp, P., Abucham, J.
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<strong>Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of prophet of Pit-1 presenting as constitutional growth delay.</strong>
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J. Clin. Endocr. Metab. 88: 38-44, 2003.
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[Full Text: https://doi.org/10.1210/jc.2001-011872]
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Wu, W., Cogan, J. D., Pfaffle, R. W., Dasen, J. S., Frisch, H., O'Connell, S. M., Flynn, S. E., Brown, M. R., Mullis, P. E., Parks, J. S., Phillips, J. A., III, Rosenfeld, M. G.
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<strong>Mutations in PROP1 cause familial combined pituitary hormone deficiency.</strong>
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Nature Genet. 18: 147-149, 1998.
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[PubMed: 9462743]
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[Full Text: https://doi.org/10.1038/ng0298-147]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Carol A. Bocchini - updated : 05/23/2020<br>Marla J. F. O'Neill - updated : 10/2/2009<br>George E. Tiller - updated : 5/22/2007<br>John A. Phillips, III - updated : 5/11/2006<br>John A. Phillips, III - updated : 4/7/2006<br>John A. Phillips, III - updated : 4/6/2006<br>Victor A. McKusick - updated : 12/5/2005<br>John A. Phillips, III - updated : 7/21/2005<br>John A. Phillips, III - updated : 6/29/2005<br>John A. Phillips, III - updated : 4/8/2005<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 3/22/2002<br>John A. Phillips, III - updated : 3/21/2002<br>Ada Hamosh - updated : 11/26/2001<br>George E. Tiller - updated : 10/15/2001<br>John A. Phillips, III - updated : 10/10/2001<br>John A. Phillips, III - updated : 3/7/2001<br>John A. Phillips, III - updated : 3/20/2000<br>John A. Phillips, III - updated : 10/14/1999<br>John A. Phillips, III - updated : 9/20/1999<br>John A. Phillips, III - revised : 9/3/1999<br>John A. Phillips, III - reorganized : 9/3/1999<br>John A. Phillips, III - updated : 3/19/1999<br>John A. Phillips, III - updated : 3/3/1999<br>John A. Phillips, III - updated : 2/9/1999<br>Victor A. McKusick - updated : 1/28/1998<br>Victor A. McKusick - updated : 1/23/1998<br>John A. Phillips, III - updated : 1/8/1997
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Victor A. McKusick : 11/27/1996
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