5913 lines
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Entry
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- *188830 - PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE I, ALPHA; PRKAR1A
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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">*188830</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/188830">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000108946;t=ENST00000589228" 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=5573" 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=188830" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000108946;t=ENST00000589228" 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_001276289,NM_001276290,NM_001278433,NM_001369389,NM_001369390,NM_002734,NM_212471,NM_212472,XM_011524984,XM_047436369,XM_047436370" 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_002734" 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=188830" 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=01786&isoform_id=01786_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/PRKAR1A" 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/125193,179895,179922,490118,1658306,4506063,15705885,23273780,47132581,47132583,51476352,62205278,86440173,86440175,86440177,119609466,119609467,119609468,119609469,119609470,119609471,189065393,193783578,308219414,443497964,443497966,510025468,767995236,1609038691,1609040171,2217312739,2217312741,2462556339,2462556341,2462556343" 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/P10644" 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=5573" 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=ENSG00000108946;t=ENST00000589228" 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=PRKAR1A" 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=PRKAR1A" 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+5573" 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/PRKAR1A" 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:5573" 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/5573" 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=chr17&hgg_gene=ENST00000590353.1&hgg_start=68413623&hgg_end=68551316&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:9388" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9388" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/prkar1a" 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=188830[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=188830[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/PRKAR1A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000108946" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=PRKAR1A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=PRKAR1A" 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=PRKAR1A" 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=PRKAR1A&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/PA33754" 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:9388" 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/FBgn0259243.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:104878" 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/PRKAR1A#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:104878" 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/5573/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=5573" 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=WBGene00002190;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-050116-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5573" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=PRKAR1A&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>
|
|
188830
|
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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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PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE I, ALPHA; PRKAR1A
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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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|
PROTEIN KINASE A, RI-ALPHA SUBUNIT<br />
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TISSUE-SPECIFIC EXTINGUISHER 1; TSE1
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<span class="h3 mim-font">
|
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PRKAR1A/RARA FUSION GENE, INCLUDED
|
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</span>
|
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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|
|
PTC2 CHIMERIC ONCOGENE, INCLUDED
|
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</span>
|
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</div>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PRKAR1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PRKAR1A</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/17/881?start=-3&limit=10&highlight=881">17q24.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:68413623-68551316&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'})">17:68,413,623-68,551,316</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=101800,160980,255960,610489" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/881?start=-3&limit=10&highlight=881">
|
|
17q24.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Acrodysostosis 1, with or without hormone resistance
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
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<p>PRKAR1A is a critical component of type I protein kinase A (PKA), the main mediator of cAMP signaling in mammals. PKA is a tetramer consisting of 2 regulatory and 2 catalytic subunits. It is inactive in the absence of cAMP. Activation occurs when 2 cAMP molecules bind to each regulatory subunit, eliciting a reversible conformational change that releases active catalytic subunits. Four distinct regulatory subunits of PKA have been identified: RI-alpha, RI-beta (<a href="/entry/176911">176911</a>), RII-alpha (<a href="/entry/176910">176910</a>), and RII-beta (<a href="/entry/176912">176912</a>). Phosphorylation mediated by the cAMP/PKA signaling pathway is involved in the regulation of metabolism, cell proliferation, differentiation, and apoptosis (review by <a href="#7" class="mim-tip-reference" title="Bossis, I., Stratakis, C. A. <strong>PRKAR1A: normal and abnormal functions.</strong> Endocrinology 145: 5452-5458, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15331577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15331577</a>] [<a href="https://doi.org/10.1210/en.2004-0900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15331577">Bossis and Stratakis, 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15331577" 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>Extinction is an operational term that refers to the lack of expression of tissue-specific traits and is generally observed in hybrid cells formed by fusing dissimilar cell types. <a href="#22" class="mim-tip-reference" title="Killary, A. M., Fournier, R. E. K. <strong>A genetic analysis of extinction: trans-dominant loci regulate expression of liver-specific traits in hepatoma hybrid cells.</strong> Cell 38: 523-534, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6147198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6147198</a>] [<a href="https://doi.org/10.1016/0092-8674(84)90507-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6147198">Killary and Fournier (1984)</a> studied extinction of liver-specific tyrosine aminotransferase (<a href="/entry/613018">613018</a>) when rat hepatoma cells were fused with mouse fibroblasts. By microcell hybrids, they showed that mouse chromosome 11 was specifically responsible for extinction and that homologous human chromosome 17 had the same activity. The tissue-specific extinguisher-1 locus (Tse1) in the mouse represses gene expression in trans. To search for other Tse1-responsive genes, <a href="#28" class="mim-tip-reference" title="Lem, J., Chin, A. C., Thayer, M. J., Leach, R. J., Fournier, R. E. K. <strong>Coordinate regulation of two genes encoding gluconeogenic enzymes by the trans-dominant locus Tse-1.</strong> Proc. Nat. Acad. Sci. 85: 7302-7306, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2902627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2902627</a>] [<a href="https://doi.org/10.1073/pnas.85.19.7302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2902627">Lem et al. (1988)</a> screened for expression of liver-specific mRNAs in hepatoma microcell hybrids containing mouse chromosome 11 or human chromosome 17. Whereas most liver gene activity was unaffected in such hybrids, phosphoenolpyruvate carboxykinase (<a href="/entry/261650">261650</a>, <a href="/entry/261680">261680</a>) and tyrosine aminotransferase gene expression was coordinately repressed in these clones. Extinction of both genes was apparently mediated by a single genetic locus that resides on human chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6147198+2902627" 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="#34" class="mim-tip-reference" title="Sandberg, M., Tasken, K., Oyen, O., Hansson, V., Jahnsen, T. <strong>Molecular cloning, cDNA structure and deduced amino acid sequence for a type I regulatory subunit of cAMP-dependent protein kinase from human testis.</strong> Biochem. Biophys. Res. Commun. 149: 939-945, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3426618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3426618</a>] [<a href="https://doi.org/10.1016/0006-291x(87)90499-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3426618">Sandberg et al. (1987)</a> cloned the regulatory subunit of type I cAMP-dependent protein kinase A from a human testis cDNA library. The cDNA encodes a deduced 381-amino acid protein. Northern blot analysis demonstrated 1.5- and 3.0-kb mRNA transcripts in human testis and a 3.0-kb transcript in human T lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3426618" 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="Boshart, M., Weih, F., Nichols, M., Schutz, G. <strong>The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase.</strong> Cell 66: 849-859, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1832337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1832337</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90432-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1832337">Boshart et al. (1991)</a> identified the regulatory subunit RI-alpha of PKA as the product of the TSE1 locus. The evidence consisted of concordant expression of RI-alpha mRNA and TSE1 genetic activity, high resolution physical mapping of the 2 genes on human chromosome 17, and the ability of transfected RI-alpha cDNA to generate a phenocopy of TSE1-mediated extinction. <a href="#21" class="mim-tip-reference" title="Jones, K. W., Shapero, M. H., Chevrette, M., Fournier, R. E. K. <strong>Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A.</strong> Cell 66: 861-872, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1889088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1889088</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90433-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1889088">Jones et al. (1991)</a> independently established identity of TSE1 and the RI-alpha subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1832337+1889088" 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="Catalano, A., Dawson, M. A., Somana, K., Opat, S., Schwarer, A., Campbell, L. J., Iland, H. <strong>The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia.</strong> Blood 110: 4073-4076, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17712046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17712046</a>] [<a href="https://doi.org/10.1182/blood-2007-06-095554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17712046">Catalano et al. (2007)</a> noted that the PRKAR1A gene maps to chromosome 17q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17712046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Amieux, P. S., Howe, D. G., Knickerbocker, H., Lee, D. C., Su, T., Laszlo, G. S., Idzerda, R. L., McKnight, G. S. <strong>Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo.</strong> J. Biol. Chem. 277: 27294-27304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12004056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12004056</a>] [<a href="https://doi.org/10.1074/jbc.M200302200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12004056">Amieux et al. (2002)</a> presented evidence indicating that increased basal PKA activity resulting from targeted disruption of the mouse RI-alpha isoform affects signaling in the primitive streak, causing profound deficits in the production of all mesoderm derivatives including the heart. In contrast, disruption of the RII-alpha subunit did not result in any developmental defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12004056" 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="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> showed that PKA and casein kinase I (CKI; <a href="/entry/600505">600505</a>) regulate Smo (<a href="/entry/601500">601500</a>) cell surface accumulation and activity in response to hedgehog (Hh; see <a href="/entry/600725">600725</a>). Blocking PKA or CKI activity in the Drosophila wing disc prevented Hh-induced Smo accumulation and attenuated pathway activity, whereas increasing PKA activity promoted Smo accumulation and pathway activation. <a href="#20" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> showed that PKA and CKI phosphorylate Smo at several sites, and that phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal. Conversely, phosphorylation-mimicking Smo variants showed constitutive cell surface expression and signaling activity. Furthermore, <a href="#20" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> found that the levels of Smo cell surface expression and activity correlated with its levels of phosphorylation. <a href="#20" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> concluded that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell surface levels and signaling activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunofluorescent and confocal microscopy, <a href="#13" class="mim-tip-reference" title="Durick, K., Gill, G. N., Taylor, S. S. <strong>Shc and Enigma are both required for mitogenic signaling by Ret/ptc2.</strong> Molec. Cell. Biol. 18: 2298-2308, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9528800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9528800</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9528800[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.18.4.2298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9528800">Durick et al. (1998)</a> demonstrated that ENIGMA (<a href="/entry/605903">605903</a>) is localized through its PDZ domain to the cell periphery and in some cytoskeletal components, and that ENIGMA colocalizes with RET/PTC2. Yeast 2-hybrid analysis showed that ENIGMA binds through its LIM2 domain to RET/PTC2 at tyr586 in a phosphorylation-independent manner, and that this interaction, as well as binding by SHC1 (<a href="/entry/600560">600560</a>), is required for RET/PTC2 mitogenic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9528800" 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="#38" class="mim-tip-reference" title="Zhang, J., Hupfeld, C. J., Taylor, S. S., Olefsky, J. M., Tsien, R. Y. <strong>Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes.</strong> Nature 437: 569-573, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177793</a>] [<a href="https://doi.org/10.1038/nature04140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177793">Zhang et al. (2005)</a> showed that in adipocytes, chronically high insulin levels inhibit beta-adrenergic receptors (see <a href="/entry/109630">109630</a>), but not other cAMP-elevating stimuli, from activating PKA. They measured this using an improved fluorescent reporter and by phosphorylation of endogenous CREB (<a href="/entry/123810">123810</a>). Disruption of PKA scaffolding mimicked the interference of insulin with beta-adrenergic receptor signaling. <a href="#38" class="mim-tip-reference" title="Zhang, J., Hupfeld, C. J., Taylor, S. S., Olefsky, J. M., Tsien, R. Y. <strong>Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes.</strong> Nature 437: 569-573, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177793</a>] [<a href="https://doi.org/10.1038/nature04140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177793">Zhang et al. (2005)</a> suggested that chronically high insulin levels may disrupt the close apposition of beta-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177793" 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="#12" class="mim-tip-reference" title="Dodge-Kafka, K. L., Soughayer, J., Pare, G. C., Michel, J. J. C., Langeberg, L. K., Kapiloff, M. S., Scott, J. D. <strong>The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways.</strong> Nature 437: 574-578, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16177794[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177794">Dodge-Kafka et al. (2005)</a> identified a cAMP-responsive signaling complex maintained by the muscle-specific A-kinase anchoring protein (AKAP6; <a href="/entry/604691">604691</a>) that includes PKA, PDE4D3 (<a href="/entry/600129">600129</a>), and EPAC1 (<a href="/entry/606057">606057</a>). These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an AKAP6-associated ERK5 (<a href="/entry/602521">602521</a>) kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits EPAC1, an exchange factor for the small GTPase RAP1 (<a href="/entry/179520">179520</a>), to enable cAMP-dependent attenuation of ERK5. Pharmacologic and molecular manipulations of the AKAP6 complex showed that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, <a href="#12" class="mim-tip-reference" title="Dodge-Kafka, K. L., Soughayer, J., Pare, G. C., Michel, J. J. C., Langeberg, L. K., Kapiloff, M. S., Scott, J. D. <strong>The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways.</strong> Nature 437: 574-578, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16177794[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177794">Dodge-Kafka et al. (2005)</a> concluded that 2 coupled cAMP-dependent feedback loops are coordinated within the context of the AKAP6 complex, suggesting that local control of cAMP signaling by AKAP proteins is more intricate than had been appreciated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a combination of in vitro explant assays, mutant analysis, and gene delivery into mouse embryos cultured ex vivo, <a href="#10" class="mim-tip-reference" title="Chen, A. E., Ginty, D. D., Fan, C.-M. <strong>Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins.</strong> Nature 433: 317-322, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15568017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15568017</a>] [<a href="https://doi.org/10.1038/nature03126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15568017">Chen et al. (2005)</a> demonstrated that adenylyl cyclase (see <a href="/entry/103072">103072</a>) signaling through PKA and its target transcription factor CREB are required for Wnt (see <a href="/entry/164820">164820</a>)-directed myogenic gene expression. Wnt proteins can also stimulate CREB-mediated transcription, providing evidence for a Wnt signaling pathway involving PKA and CREB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15568017" 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="#3" class="mim-tip-reference" title="Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Ranganath, S., Li, G., Schrum, J. P., Manis, J. P., Alt, F. W. <strong>The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation.</strong> Nature 438: 508-511, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251902</a>] [<a href="https://doi.org/10.1038/nature04255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251902">Basu et al. (2005)</a> showed that activation-induced cytidine deaminase (AID; <a href="/entry/605257">605257</a>) from B cells is phosphorylated on a consensus PKA site and that PKA is the physiologic AID kinase. <a href="#3" class="mim-tip-reference" title="Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Ranganath, S., Li, G., Schrum, J. P., Manis, J. P., Alt, F. W. <strong>The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation.</strong> Nature 438: 508-511, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251902</a>] [<a href="https://doi.org/10.1038/nature04255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251902">Basu et al. (2005)</a> showed that AID from nonlymphoid cells can be functionally phosphorylated by recombinant PKA to allow interaction with replication protein A (RPA; see <a href="/entry/179835">179835</a>) and promote deamination of transcribed double-stranded DNA (dsDNA) substrates. Moreover, mutation of the major PKA phosphorylation site of AID preserves single-stranded DNA (ssDNA) deamination activity, but markedly reduces RPA-dependent dsDNA deamination activity and severely impairs the ability of AID to effect class switch recombination in vivo. <a href="#3" class="mim-tip-reference" title="Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Ranganath, S., Li, G., Schrum, J. P., Manis, J. P., Alt, F. W. <strong>The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation.</strong> Nature 438: 508-511, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251902</a>] [<a href="https://doi.org/10.1038/nature04255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251902">Basu et al. (2005)</a> concluded that PKA has a critical role in posttranslational regulation of AID activity in B cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251902" 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="#36" class="mim-tip-reference" title="Schernthaner-Reiter, M. H., Trivellin, G., Stratakis, C. A. <strong>Interaction of AIP with protein kinase A (cAMP-dependent protein kinase).</strong> Hum. Molec. Genet. 27: 2604-2613, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29726992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29726992</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29726992[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddy166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29726992">Schernthaner-Reiter et al. (2018)</a> found that endogenous Aip (<a href="/entry/605555">605555</a>) physically interacted and colocalized with R1-alpha and C-alpha (PRKACA; <a href="/entry/601639">601639</a>) in the cytoplasm of rat mammosomatotropinoma cell line GH3. Fractionation analysis showed that all 3 proteins localized to cytoplasm and membranes of GH3 cells. Aip interacted with R1-alpha and C-alpha separately and in a 3-protein complex. Aip overexpression reduced PKA activity in GH3 cells. C-alpha overexpression stabilized both Aip and R1-alpha protein levels independent of PKA activity. Aip protein level was regulated by translation and degradation via the ubiquitin/proteasome pathway. Aip knockdown modestly increased PKA activity in GH3 cells. Further analysis revealed that Aip functionally interacted with PDE-dependent PKA pathway activity via Pde4 (<a href="/entry/600126">600126</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29726992" 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="#23" class="mim-tip-reference" title="Kim, C., Xuong, N.-H., Taylor, S. S. <strong>Crystal structure of a complex between the catalytic and regulatory (RI-alpha) subunits of PKA.</strong> Science 307: 690-696, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15692043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15692043</a>] [<a href="https://doi.org/10.1126/science.1104607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15692043">Kim et al. (2005)</a> determined the crystal structure of the cAMP-dependent protein kinase catalytic subunit bound to a deletion mutant of the regulatory subunit (RI-alpha) at 2.0-angstrom resolution. This structure defines a previously unidentified extended interface in which the large lobe of the catalytic subunit is like a stable scaffold where tyr247 in the G helix and trp196 in the phosphorylated activation loop serve as anchor points for binding the RI-alpha subunit. These residues compete with cAMP for the phosphate-binding cassette in RI-alpha. In contrast to this catalytic subunit, RI-alpha undergoes major conformational changes when the complex is compared with cAMP-bound RI-alpha. <a href="#23" class="mim-tip-reference" title="Kim, C., Xuong, N.-H., Taylor, S. S. <strong>Crystal structure of a complex between the catalytic and regulatory (RI-alpha) subunits of PKA.</strong> Science 307: 690-696, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15692043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15692043</a>] [<a href="https://doi.org/10.1126/science.1104607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15692043">Kim et al. (2005)</a> concluded that the complex provides a molecular mechanism for inhibition of PKA and suggests how cAMP binding leads to activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15692043" 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>Papillary thyroid carcinoma (see <a href="/entry/188550">188550</a>) can be caused by chimeric oncogenes formed by fusion of the tyrosine kinase domain of the RET protooncogene (<a href="/entry/164761">164761</a>) to the 5-prime terminal region of another gene. See, for example, PTC1 (<a href="/entry/601985">601985</a>). <a href="#5" class="mim-tip-reference" title="Bongarzone, I., Monzini, N., Borrello, M. G., Carcano, C., Ferraresi, G., Arighi, E., Mondellini, P., Della Porta, G., Pierotti, M. A. <strong>Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A.</strong> Molec. Cell. Biol. 13: 358-366, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678053</a>] [<a href="https://doi.org/10.1128/mcb.13.1.358-366.1993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678053">Bongarzone et al. (1993)</a> isolated and sequenced a type of RET oncogenic rearrangement involving the TSE1 gene. Analysis of the nucleotide sequence indicated that the transforming activity was created by the fusion of the RET tyrosine kinase domain with part of the RI-alpha regulatory subunit of PKA. The authors stated that this was the first example of an oncogenic activity involving a PKA gene. The chimeric oncogene formed by the fusion of the RET and TSE1 genes is known as PTC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7678053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Catalano, A., Dawson, M. A., Somana, K., Opat, S., Schwarer, A., Campbell, L. J., Iland, H. <strong>The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia.</strong> Blood 110: 4073-4076, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17712046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17712046</a>] [<a href="https://doi.org/10.1182/blood-2007-06-095554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17712046">Catalano et al. (2007)</a> reported a 66-year-old man with acute promyelocytic leukemia (APL) who was found to have a PRKAR1A/RARA (<a href="/entry/180240">180240</a>) fusion gene, possibly resulting from an insertion of RARA distal to PRKAR1A, followed by a deletion of 3-prime PRKAR1A, 5-prime RARA, and any intervening sequences. The fusion transcript resulted from cryptic splicing of the first 100 bases of PRKAR1A exon 3 to the 5-prime end of RARA exon 3, and predicted a 495-amino acid fusion protein. The C-terminal end of RARA involved is that shared by all RARA rearrangements in APL. The patient had a good response to chemotherapy with complete remission of the disease by 11 months. <a href="#9" class="mim-tip-reference" title="Catalano, A., Dawson, M. A., Somana, K., Opat, S., Schwarer, A., Campbell, L. J., Iland, H. <strong>The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia.</strong> Blood 110: 4073-4076, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17712046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17712046</a>] [<a href="https://doi.org/10.1182/blood-2007-06-095554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17712046">Catalano et al. (2007)</a> postulated that fusion of the R1-alpha dimerization domain to RARA may be involved in deregulation of PKA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17712046" 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><strong><em>Carney Complex Type 1</em></strong></p><p>
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Carney complex (see CNC1, <a href="/entry/160980">160980</a>) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas. Because of its similarities to the McCune-Albright syndrome (MAS; <a href="/entry/174800">174800</a>) and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signaling were thought to be candidates for the site of mutation(s) in Carney complex (<a href="#11" class="mim-tip-reference" title="DeMarco, L., Stratakis, C. A., Boson, W. L., Jakbovitz, O., Carson, E., Andrade, L. M., Amaral, V. F., Rocha, J. L., Choursos, G. P., Nordenskjold, M., Friedman, E. <strong>Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs-alpha gene.</strong> Hum. Genet. 98: 185-188, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8698339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8698339</a>] [<a href="https://doi.org/10.1007/s004390050187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8698339">DeMarco et al., 1996</a>). In tumor tissue from Carney complex families mapping to 17q, <a href="#24" class="mim-tip-reference" title="Kirschner, L. S., Carney, J. A., Pack, S. D., Taymans, S. E., Giatzakis, C., Cho, Y. S., Cho-Chung, Y. S., Stratakis, C. A. <strong>Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.</strong> Nature Genet. 26: 89-92, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973256</a>] [<a href="https://doi.org/10.1038/79238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973256">Kirschner et al. (2000)</a> detected loss of heterozygosity (LOH) in the vicinity of the PRKAR1A gene, including a polymorphic site within its 5-prime region. In affected members of 3 unrelated kindreds, they identified a germline mutation in the PRKAR1A gene (<a href="#0001">188830.0001</a>). Analysis of additional cases demonstrated the same mutation in a sporadic case of Carney complex, and different mutations in 3 other families, including 1 with isolated inherited cardiac myxomas (<a href="#0002">188830.0002</a>-<a href="#0004">188830.0004</a>). Analysis of protein kinase A (PKA) activity in Carney complex tumors demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-Carney complex tumors. <a href="#24" class="mim-tip-reference" title="Kirschner, L. S., Carney, J. A., Pack, S. D., Taymans, S. E., Giatzakis, C., Cho, Y. S., Cho-Chung, Y. S., Stratakis, C. A. <strong>Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.</strong> Nature Genet. 26: 89-92, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973256</a>] [<a href="https://doi.org/10.1038/79238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973256">Kirschner et al. (2000)</a> concluded that germline mutations in PRKAR1A, an apparent tumor-suppressor gene, are responsible for the Carney complex phenotype in a subset of patients with that disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10973256+8698339" 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>Independently, <a href="#8" class="mim-tip-reference" title="Casey, M., Vaughan, C. J., He, J., Hatcher, C. J., Winter, J. M., Weremowicz, S., Montgomery, K., Kucherlapati, R., Morton, C. C., Basson, C. T. <strong>Mutations in the protein kinase A R1-alpha regulatory subunit cause familial cardiac myxomas and Carney complex.</strong> J. Clin. Invest. 106: R31-R38, 2000. Note: Erratum: J. Clin. Invest. 107: 235 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10974026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10974026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10974026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI10841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10974026">Casey et al. (2000)</a> had noted from a search of the Human Genome Project databases that the PRKAR1A gene is included within the minimal interval for the Carney complex locus on 17q. Furthermore, they noted that a human genomic BAC clone contained sequences corresponding to both PRKAR1A and an anonymous marker that exhibited no recombination with the Carney complex gene in families they had studied. Therefore, the PRKAR1A chromosomal location, the known role of PKA in signal transduction and cell growth, and the ubiquitous expression pattern of the R1-alpha subunit all suggested this gene as a candidate for Carney complex. In affected members of 3 unrelated families, they demonstrated PRKAR1A frameshift mutations resulting in haploinsufficiency of R1-alpha (<a href="#0005">188830.0005</a>-<a href="#0007">188830.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10974026" 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="Kirschner, L. S., Sandrini, F., Monbo, J., Lin, J.-P., Carney, J. A., Stratakis, C. A. <strong>Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex.</strong> Hum. Molec. Genet. 9: 3037-3046, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11115848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11115848</a>] [<a href="https://doi.org/10.1093/hmg/9.20.3037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11115848">Kirschner et al. (2000)</a> identified the PRKAR1A genomic structure, screened for mutations in 34 CNC families and 20 patients with sporadic disease, and confirmed the genetic heterogeneity of CNC. Altogether, 15 distinct PRKAR1A mutations were identified in 22 (41%) of 54 kindreds. In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay (NMD). Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. The authors concluded that all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. Six families mapped to the CNC2 locus (<a href="/entry/605244">605244</a>) on 2p16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11115848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Robinson-White, A., Hundley, T. R., Shiferaw, M., Bertherat, J., Sandrini, F., Stratakis, C. A. <strong>Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2.</strong> Hum. Molec. Genet. 12: 1475-1484, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812976</a>] [<a href="https://doi.org/10.1093/hmg/ddg160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812976">Robinson-White et al. (2003)</a> determined that PKA activity both at baseline and after stimulation with cAMP was augmented in cells carrying PRKAR1A mutations. Quantitative message analysis showed that the main PKA subunits expressed were type I (RI-alpha and RI-beta), but RI-alpha was decreased in mutant cells. Immunoblot assays of ERK1/2 (<a href="/entry/601795">601795</a>, <a href="/entry/176948">176948</a>) phosphorylation by the cell- and pathway-specific stimulant lysophosphatidic acid (LPA) showed activation of this pathway in a time- and concentration-dependent manner that was prevented by a specific inhibitor. There was a greater rate of growth in mutant cells; forskolin and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal but not in mutant cells. Forskolin inhibited LPA-induced cell proliferation and metabolism in normal cells, but stimulated these parameters in mutant cells. These data were also replicated in a pituitary tumor cell line carrying the most common PRKAR1A mutation, 578delTG (<a href="#0001">188830.0001</a>), and an in vitro construct of mutant PRKAR1A that was shown to lead to augmented PKA-mediated phosphorylation. <a href="#32" class="mim-tip-reference" title="Robinson-White, A., Hundley, T. R., Shiferaw, M., Bertherat, J., Sandrini, F., Stratakis, C. A. <strong>Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2.</strong> Hum. Molec. Genet. 12: 1475-1484, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812976</a>] [<a href="https://doi.org/10.1093/hmg/ddg160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812976">Robinson-White et al. (2003)</a> concluded that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism, and proliferation. They speculated that reversal of PKA-mediated inhibition of this MAPK pathway in CNC cells may contribute to tumorigenesis in this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12812976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Robinson-White, A., Meoli, E., Stergiopoulos, S., Horvath, A., Boikos, S., Bossis, I., Stratakis, C. A. <strong>PRKAR1A mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex.</strong> J. Clin. Endocr. Metab. 91: 2380-2388, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16569736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16569736</a>] [<a href="https://doi.org/10.1210/jc.2006-0188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16569736">Robinson-White et al. (2006)</a> investigated how PKA and its subunits and ERK1/2 and their molecular partners change in the presence of PRKAR1A mutations in adrenocortical tissue. Mutations in PRKAR1A caused increased total cAMP-stimulated kinase activity, likely the result of upregulation of other PKA subunits caused by downregulation of RI-alpha, as seen in human lymphocytes and mouse animal models. The authors concluded that these changes, associated with enhanced MAPK activity, may be, in part, responsible for the proliferative signals that result in primary pigmented nodular adrenocortical disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16569736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Veugelers, M., Wilkes, D., Burton, K., McDermott, D. A., Song, Y., Goldstein, M. M., La Perle, K., Vaughan, C. J., O'Hagan, A., Bennett, K. R., Meyer, B. J., Legius, E., and 27 others. <strong>Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.</strong> Proc. Nat. Acad. Sci. 101: 14222-14227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15371594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15371594</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15371594[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405535101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15371594">Veugelers et al. (2004)</a> performed mutation analysis of the PRKAR1A gene in 51 unrelated probands with Carney complex and identified mutations in 33 (65%). All mutations, except for 1 missense mutation (<a href="#0013">188830.0013</a>), led to PRKAR1A haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15371594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Greene, E. L., Horvath, A. D., Nesterova, M., Giatzakis, C., Bossis, I., Stratakis, C. A. <strong>In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay.</strong> Hum. Mutat. 29: 633-639, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18241045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18241045</a>] [<a href="https://doi.org/10.1002/humu.20688" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18241045">Greene et al. (2008)</a> identified 7 pathogenic PRKAR1A mutations (see, e.g., <a href="#0013">188830.0013</a>) that resulted in expressed mutant proteins and not premature stop codons that lead to subsequent NMD. In vitro functional expression studies showed that the mutant proteins all resulted in increased PKA activity, most likely caused by decreased binding of the mutant PRKAR1A to cAMP and/or the catalytic subunit. The findings suggested that altered PRKAR1A activity, not only haploinsufficiency, is sufficient enough to increase PKA activity, which likely results in tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18241045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Primary Pigmented Nodular Adrenocortical Disease 1</em></strong></p><p>
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<a href="#19" class="mim-tip-reference" title="Groussin, L., Kirschner, L. S., Vincent-Dejean, C., Perlemoine, K., Jullian, E., Delemer, B., Zacharieva, S., Pignatelli, D., Carney, J. A., Luton, J. P., Bertagna, X., Stratakis, C. A., Bertherat, J. <strong>Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.</strong> Am. J. Hum. Genet. 71: 1433-1442, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12424709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12424709</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12424709[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/344579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12424709">Groussin et al. (2002)</a> studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD1; <a href="/entry/601489">601489</a>) or Carney complex and found that 9 of them had PRKAR1A gene defects (including 7 novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, in 1 kindred, a splice site mutation, IVS6+1G-T (<a href="#0011">188830.0011</a>), led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear level. The authors stated that this was the first demonstration of an inactivating PRKAR1A mutation expressed at the protein level and leading to stimulation of the PKA pathway in patients with Carney complex. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis in tissues in patients with Carney complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12424709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Acrodysostosis 1</em></strong></p><p>
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In 3 unrelated patients with acrodysostosis with hormone resistance (ACRDYS1; <a href="/entry/101800">101800</a>), <a href="#30" class="mim-tip-reference" title="Linglart, A., Menguy, C., Couvineau, A., Auzan, C., Gunes, Y., Cancel, M., Motte, E., Pinto, G., Chanson, P., Bougneres, P., Clauser, E., Silve, C. <strong>Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance.</strong> New Eng. J. Med. 364: 2218-2226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21651393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21651393</a>] [<a href="https://doi.org/10.1056/NEJMoa1012717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21651393">Linglart et al. (2011)</a> identified a de novo truncating mutation in the PRKAR1A gene (R368X; <a href="#0015">188830.0015</a>). The mutation resulted in decreased protein kinase A sensitivity to cAMP, causing multiple hormone resistance and skeletal anomalies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21651393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Systemic Lupus Erythematosus</em></strong></p><p>
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Systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>) is an autoimmune disorder characterized by diverse dysfunctions of immune effector cells, including proliferation and cytotoxicity. In T cells from patients with SLE, activity of type 1 protein kinase A isozymes is greatly reduced because of decreased expression of the alpha and beta regulatory subunits. <a href="#26" class="mim-tip-reference" title="Laxminarayana, D., Khan, I. U., Kammer, G. M. <strong>Transcript mutations of the alpha regulatory subunit of protein kinase A and up-regulation of the RNA-editing gene transcript in lupus T lymphocytes.</strong> Lancet 360: 842-849, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12243919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12243919</a>] [<a href="https://doi.org/10.1016/s0140-6736(02)09966-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12243919">Laxminarayana et al. (2002)</a> cloned and sequenced cDNA of PRKAR1A and corresponding genomic DNA of the coding region to detect sequence changes from 8 patients with SLE and 6 healthy controls. Various transcript mutations, including deletions, transitions, and transversions, were found at a frequency 7.5 times higher than that in control T cells. By contrast, no genomic mutations were identified. Because transcript editing is regulated by adenosine deaminases that act on RNA (ADAR; <a href="/entry/146920">146920</a>), they quantified expression of ADAR1 transcripts in SLE and control cells, finding that ADAR1 mRNA content was 3.5 times higher in SLE cells than in control T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12243919" 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>Because they had identified 24 mutations in the PRKAR1A gene in 33 of 51 (65%) unrelated probands with Carney complex, all but 1 of which resulted in haploinsufficiency, <a href="#37" class="mim-tip-reference" title="Veugelers, M., Wilkes, D., Burton, K., McDermott, D. A., Song, Y., Goldstein, M. M., La Perle, K., Vaughan, C. J., O'Hagan, A., Bennett, K. R., Meyer, B. J., Legius, E., and 27 others. <strong>Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.</strong> Proc. Nat. Acad. Sci. 101: 14222-14227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15371594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15371594</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15371594[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405535101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15371594">Veugelers et al. (2004)</a> studied the consequences of Prkar1a haploinsufficiency in mice. Although they did not observe cardiac myxomas or altered pigmentation in Prkar1a +/- mice, they did observe some phenotypes similar to Carney complex, including altered heart rate variability. Moreover, Prkar1a +/- mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from Prkar1a +/- mice did not exhibit Prkar1a loss of heterozygosity. <a href="#37" class="mim-tip-reference" title="Veugelers, M., Wilkes, D., Burton, K., McDermott, D. A., Song, Y., Goldstein, M. M., La Perle, K., Vaughan, C. J., O'Hagan, A., Bennett, K. R., Meyer, B. J., Legius, E., and 27 others. <strong>Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.</strong> Proc. Nat. Acad. Sci. 101: 14222-14227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15371594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15371594</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15371594[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405535101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15371594">Veugelers et al. (2004)</a> concluded that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15371594" 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="#16" class="mim-tip-reference" title="Griffin, K. J., Kirschner, L. S., Matyakhina, L., Stergiopoulos, S. G., Robinson-White, A., Lenherr, S. M., Weinberg, F. D., Claflin, E. S., Batista, D., Bourdeau, I., Voutetakis, A., Sandrini, F., Meoli, E. M., Bauer, A. J., Cho-Chung, Y. S., Bornstein, S. R., Carney, J. A., Stratakis, C. A. <strong>A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.</strong> J. Med. Genet. 41: 923-931, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15591278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15591278</a>] [<a href="https://doi.org/10.1136/jmg.2004.028043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15591278">Griffin et al. (2004)</a> created a transgenic mouse model carrying an antisense transgene for Prkar1a, resulting in an approximately 50% decrease in protein levels similar to haploinsufficiency. The transgenic mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, hypercorticosteronemia, late-onset weight gain, visceral adiposity, and mesenchymal tumors. The thyroid and adrenocortical tumors showed loss of heterozygosity at the Prkar1a locus. <a href="#16" class="mim-tip-reference" title="Griffin, K. J., Kirschner, L. S., Matyakhina, L., Stergiopoulos, S. G., Robinson-White, A., Lenherr, S. M., Weinberg, F. D., Claflin, E. S., Batista, D., Bourdeau, I., Voutetakis, A., Sandrini, F., Meoli, E. M., Bauer, A. J., Cho-Chung, Y. S., Bornstein, S. R., Carney, J. A., Stratakis, C. A. <strong>A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.</strong> J. Med. Genet. 41: 923-931, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15591278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15591278</a>] [<a href="https://doi.org/10.1136/jmg.2004.028043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15591278">Griffin et al. (2004)</a> suggested that the transgenic mice displayed several findings seen in patients with Carney complex, supporting the role of PRKAR1A as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15591278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Almeida, M. Q., Muchow, M., Boikos, S., Bauer, A. J., Griffin, K. J., Tsang, K. M., Cheadle, C., Watkins, T., Wen, F., Starost, M. F., Bossis, I., Nesterova, M., Stratakis, C. A. <strong>Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/- or Rb1+/- backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling.</strong> Hum. Molec. Genet. 19: 1387-1398, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20080939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20080939</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20080939[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20080939">Almeida et al. (2010)</a> investigated Prkar1a +/- mice when bred within the Rb1 +/- (<a href="/entry/614041">614041</a>) or Trp53 +/- (<a href="/entry/191170">191170</a>) backgrounds, or treated with a 2-step skin carcinogenesis protocol. Prkar1a +/- Trp53 +/- mice developed more sarcomas than Trp53 +/- mice (p less than 0.05), and Prkar1a +/- Rb1 +/- mice grew more (and larger) pituitary and thyroid tumors than Rb1 +/- mice. All mice with double heterozygosity had significantly reduced life spans compared with their single-heterozygous counterparts. Prkar1a +/- mice also developed more papillomas than wildtype animals. A whole-genome transcriptome profiling of tumors produced by all 3 models identified Wnt signaling as the main pathway activated by abnormal cAMP signaling, along with cell cycle abnormalities. siRNA downregulation of Ctnnb1 (<a href="/entry/116806">116806</a>), E2f1 (<a href="/entry/189971">189971</a>), or Cdk4 (<a href="/entry/123829">123829</a>) inhibited proliferation of human adrenal cells bearing a PRKAR1A-inactivating mutation and Prkar1a +/- mouse embryonic fibroblasts and arrested both cell lines at the G0/G1 phase of the cell cycle. <a href="#1" class="mim-tip-reference" title="Almeida, M. Q., Muchow, M., Boikos, S., Bauer, A. J., Griffin, K. J., Tsang, K. M., Cheadle, C., Watkins, T., Wen, F., Starost, M. F., Bossis, I., Nesterova, M., Stratakis, C. A. <strong>Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/- or Rb1+/- backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling.</strong> Hum. Molec. Genet. 19: 1387-1398, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20080939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20080939</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20080939[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20080939">Almeida et al. (2010)</a> concluded that Prkar1a haploinsufficiency is a relatively weak tumorigenic signal that can act synergistically with other tumor suppressor gene defects or chemicals to induce tumors, mostly through Wnt-signaling activation and cell cycle dysregulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20080939" 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">rs281864790 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864790;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=rs281864790" 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=rs281864790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of 2 unrelated families with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#24" class="mim-tip-reference" title="Kirschner, L. S., Carney, J. A., Pack, S. D., Taymans, S. E., Giatzakis, C., Cho, Y. S., Cho-Chung, Y. S., Stratakis, C. A. <strong>Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.</strong> Nature Genet. 26: 89-92, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973256</a>] [<a href="https://doi.org/10.1038/79238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973256">Kirschner et al. (2000)</a> identified a heterozygous 2-bp deletion (578delTG) in exon 4B of the PRKAR1A gene, resulting in a frameshift and premature termination of the protein before the cAMP binding domain. The families did not share the same chromosome 17 haplotype on the disease-bearing allele. The 2-bp deletion was also found in a third family and in a sporadic case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973256" 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 affected members of a family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#24" class="mim-tip-reference" title="Kirschner, L. S., Carney, J. A., Pack, S. D., Taymans, S. E., Giatzakis, C., Cho, Y. S., Cho-Chung, Y. S., Stratakis, C. A. <strong>Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.</strong> Nature Genet. 26: 89-92, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973256</a>] [<a href="https://doi.org/10.1038/79238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973256">Kirschner et al. (2000)</a> identified a heterozygous 889GG-CT change in exon 8 of the PRKAR1A gene, leading to premature termination after residue 204 and truncation of the N terminus at the second cAMP binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0003" class="mim-anchor"></a>
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<strong>.0003 CARNEY COMPLEX, TYPE 1</strong>
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PRKAR1A, IVS8DS, A-G, +3
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs281864799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864799;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=rs281864799" 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=rs281864799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013500 OR RCV001857341 OR RCV004649063" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013500, RCV001857341, RCV004649063" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013500...</a>
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<p>In affected members of a family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#24" class="mim-tip-reference" title="Kirschner, L. S., Carney, J. A., Pack, S. D., Taymans, S. E., Giatzakis, C., Cho, Y. S., Cho-Chung, Y. S., Stratakis, C. A. <strong>Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.</strong> Nature Genet. 26: 89-92, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973256</a>] [<a href="https://doi.org/10.1038/79238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973256">Kirschner et al. (2000)</a> identified a heterozygous A-to-G transition at position +3 of intron 8 of the PRKAR1A gene, presumably resulting in a defect in splicing of the protein product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0004" class="mim-anchor"></a>
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<strong>.0004 MYXOMA, INTRACARDIAC</strong>
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PRKAR1A, 4-BP DEL, 617TTAT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs281864791 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864791;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=rs281864791" 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=rs281864791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013501" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013501" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013501</a>
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</span>
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<span class="mim-text-font">
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<p>In affected members of a family segregating cardiac myxomas (<a href="/entry/255960">255960</a>) and no other features of Carney complex (CNC1; <a href="/entry/160980">160980</a>), originally reported by <a href="#29" class="mim-tip-reference" title="Liebler, G. A., Magovern, G. J., Park, S. B., Cushing, W. J., Begg, F. R., Joyner, C. R. <strong>Familial myxomas in four siblings.</strong> J. Thorac. Cardiovasc. Surg. 71: 605-608, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1263542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1263542</a>]" pmid="1263542">Liebler et al. (1976)</a>, <a href="#24" class="mim-tip-reference" title="Kirschner, L. S., Carney, J. A., Pack, S. D., Taymans, S. E., Giatzakis, C., Cho, Y. S., Cho-Chung, Y. S., Stratakis, C. A. <strong>Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.</strong> Nature Genet. 26: 89-92, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973256</a>] [<a href="https://doi.org/10.1038/79238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973256">Kirschner et al. (2000)</a> identified a heterozygous 4-bp deletion, 617TTAT, in exon 5 of the PRKAR1A gene. The deletion resulted in a frameshift after residue 204 and a stop codon after 26 missense residues. The mutation would abolish the second cAMP-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1263542+10973256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 CARNEY COMPLEX, TYPE 1</strong>
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</span>
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</h4>
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</div>
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<div style="float: left;">
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PRKAR1A, 1-BP DEL, 710G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs727503379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs727503379;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=rs727503379" 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=rs727503379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000151681 OR RCV000317950 OR RCV001382880" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000151681, RCV000317950, RCV001382880" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000151681...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#8" class="mim-tip-reference" title="Casey, M., Vaughan, C. J., He, J., Hatcher, C. J., Winter, J. M., Weremowicz, S., Montgomery, K., Kucherlapati, R., Morton, C. C., Basson, C. T. <strong>Mutations in the protein kinase A R1-alpha regulatory subunit cause familial cardiac myxomas and Carney complex.</strong> J. Clin. Invest. 106: R31-R38, 2000. Note: Erratum: J. Clin. Invest. 107: 235 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10974026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10974026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10974026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI10841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10974026">Casey et al. (2000)</a> demonstrated a 1-bp deletion (G) at nucleotide 710 of the PRKAR1A gene (gly208 of the protein), with a consequent frameshift and premature stop 13 codons later. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10974026" 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>
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<div>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 CARNEY COMPLEX, TYPE 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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PRKAR1A, 2-BP DEL, 845TC
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</div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013503 OR RCV003298031" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013503, RCV003298031" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013503...</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#8" class="mim-tip-reference" title="Casey, M., Vaughan, C. J., He, J., Hatcher, C. J., Winter, J. M., Weremowicz, S., Montgomery, K., Kucherlapati, R., Morton, C. C., Basson, C. T. <strong>Mutations in the protein kinase A R1-alpha regulatory subunit cause familial cardiac myxomas and Carney complex.</strong> J. Clin. Invest. 106: R31-R38, 2000. Note: Erratum: J. Clin. Invest. 107: 235 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10974026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10974026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10974026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI10841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10974026">Casey et al. (2000)</a> found a 2-bp deletion (TC) of nucleotides 845-846 at val253 of the PRKAR1A gene, with a consequent frameshift and a premature stop 15 codons later. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10974026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 CARNEY COMPLEX, TYPE 1</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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PRKAR1A, 2-BP DEL, 576TG
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013498 OR RCV000414608 OR RCV002345241" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013498, RCV000414608, RCV002345241" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013498...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#8" class="mim-tip-reference" title="Casey, M., Vaughan, C. J., He, J., Hatcher, C. J., Winter, J. M., Weremowicz, S., Montgomery, K., Kucherlapati, R., Morton, C. C., Basson, C. T. <strong>Mutations in the protein kinase A R1-alpha regulatory subunit cause familial cardiac myxomas and Carney complex.</strong> J. Clin. Invest. 106: R31-R38, 2000. Note: Erratum: J. Clin. Invest. 107: 235 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10974026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10974026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10974026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI10841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10974026">Casey et al. (2000)</a> found a 2-bp deletion (TG) of nucleotides 576-577 at thr163 of the PRKAR1A gene, resulting in a frameshift and a premature stop 6 codons later. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10974026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 CARNEY COMPLEX, TYPE 1</strong>
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</span>
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</h4>
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PRKAR1A, 88AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs281864779 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864779;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=rs281864779" 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=rs281864779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013505 OR RCV000523178" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013505, RCV000523178" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013505...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#25" class="mim-tip-reference" title="Kirschner, L. S., Sandrini, F., Monbo, J., Lin, J.-P., Carney, J. A., Stratakis, C. A. <strong>Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex.</strong> Hum. Molec. Genet. 9: 3037-3046, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11115848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11115848</a>] [<a href="https://doi.org/10.1093/hmg/9.20.3037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11115848">Kirschner et al. (2000)</a> found an A-to-G transition at nucleotide 88 of the PRKAR1A gene, abolishing the ATG translation start codon in exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11115848" 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">rs587776773 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776773;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=rs587776773" 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=rs587776773" 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=RCV000013506 OR RCV001851827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013506, RCV001851827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013506...</a>
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<p><a href="#18" class="mim-tip-reference" title="Groussin, L., Jullian, E., Perlemoine, K., Louvel, A., Leheup, B., Luton, J. P., Bertagna, X., Bertherat, J. <strong>Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease.</strong> J. Clin. Endocr. Metab. 87: 4324-4329, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213893</a>] [<a href="https://doi.org/10.1210/jc.2002-020592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213893">Groussin et al. (2002)</a> investigated the genetics of patients with sporadic and isolated primary pigmented nodular adrenocortical disease (PPNAD1; <a href="/entry/610489">610489</a>) by sequencing the PRKAR1A gene in 5 patients. Different inactivating germline mutations were found in all 5 patients. In an 18-year-old woman of African origin with ACTH-independent Cushing syndrome, who presented with a 2.5-cm macronodule of the right adrenal mimicking an adrenal adenoma, the authors found 2 mutations in the PRKAR1A gene. One was a germline point mutation in the splice donor site of exon 1B, 102G-A, that resulted in partial exon skipping. An abnormally short mRNA was predicted to impede translation into PRKAR1A protein. The second mutation was a 16-bp deletion of the acceptor splice site of exon 4B (-17 to -2) that was found only in the macronodule of the right adrenal. <a href="#18" class="mim-tip-reference" title="Groussin, L., Jullian, E., Perlemoine, K., Louvel, A., Leheup, B., Luton, J. P., Bertagna, X., Bertherat, J. <strong>Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease.</strong> J. Clin. Endocr. Metab. 87: 4324-4329, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213893</a>] [<a href="https://doi.org/10.1210/jc.2002-020592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213893">Groussin et al. (2002)</a> concluded that inactivating germline mutations of PRKAR1A are frequent in sporadic and isolated cases of PPNAD. The wildtype allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213893" 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>See <a href="#0009">188830.0009</a> and <a href="#18" class="mim-tip-reference" title="Groussin, L., Jullian, E., Perlemoine, K., Louvel, A., Leheup, B., Luton, J. P., Bertagna, X., Bertherat, J. <strong>Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease.</strong> J. Clin. Endocr. Metab. 87: 4324-4329, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213893</a>] [<a href="https://doi.org/10.1210/jc.2002-020592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213893">Groussin et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213893" 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">rs281864798 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864798;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=rs281864798" 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=rs281864798" 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=RCV000013508" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013508" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013508</a>
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<p>In a mother and son with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#19" class="mim-tip-reference" title="Groussin, L., Kirschner, L. S., Vincent-Dejean, C., Perlemoine, K., Jullian, E., Delemer, B., Zacharieva, S., Pignatelli, D., Carney, J. A., Luton, J. P., Bertagna, X., Stratakis, C. A., Bertherat, J. <strong>Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.</strong> Am. J. Hum. Genet. 71: 1433-1442, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12424709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12424709</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12424709[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/344579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12424709">Groussin et al. (2002)</a> demonstrated heterozygosity for a splice site mutation in the PRKAR1A gene, IVS6+1G-T, which led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mother had the disorder in severe form and died of a pancreatic adenocarcinoma with rapidly growing liver metastasis. She had lentigines, heart myxoma, primary pigmented nodular adrenocortical disease, toxic multinodular goiter, and ovarian cyst. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that it activated PKA signaling at the nuclear level. Along with a lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12424709" 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">rs587776774 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776774;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=rs587776774" 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=rs587776774" 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=RCV000013509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013509</a>
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<p>In 3 cases of sporadic adrenocortical tumor, <a href="#4" class="mim-tip-reference" title="Bertherat, J., Groussin, L., Sandrini, F., Matyakhina, L., Bei, T., Stergiopoulos, S., Papageorgiou, T., Bourdeau, I., Kirschner, L. S., Vincent-Dejean, C., Perlemoine, K., Gicquel, C., Bertagna, X., Stratakis, C. A. <strong>Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.</strong> Cancer Res. 63: 5308-5319, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14500362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14500362</a>]" pmid="14500362">Bertherat et al. (2003)</a> identified somatic mutations in the PRKAR1A gene, 1 of which was a splicing mutation (IVS9AS-1G-A). All 3 mutations predicted premature termination of the protein. Somatic alterations in PRKAR1A had previously been described only in thyroid tumors (<a href="#35" class="mim-tip-reference" title="Sandrini, F., Matyakhina, L., Sarlis, N. J., Kirschner, L. S., Farmakidis, C., Gimm, O., Stratakis, C. A. <strong>Regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer.</strong> Genes Chromosomes Cancer 35: 182-192, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12203783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12203783</a>] [<a href="https://doi.org/10.1002/gcc.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12203783">Sandrini et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12203783+14500362" 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> rs137853303 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853303;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/rs137853303?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=rs137853303" 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=rs137853303" 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=RCV000013510 OR RCV000148738 OR RCV001014797 OR RCV003320547 OR RCV003407324 OR RCV003466855" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013510, RCV000148738, RCV001014797, RCV003320547, RCV003407324, RCV003466855" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013510...</a>
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<p>In affected members of an English family with Carney complex (CNC1; <a href="/entry/160980">160980</a>), <a href="#37" class="mim-tip-reference" title="Veugelers, M., Wilkes, D., Burton, K., McDermott, D. A., Song, Y., Goldstein, M. M., La Perle, K., Vaughan, C. J., O'Hagan, A., Bennett, K. R., Meyer, B. J., Legius, E., and 27 others. <strong>Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.</strong> Proc. Nat. Acad. Sci. 101: 14222-14227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15371594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15371594</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15371594[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405535101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15371594">Veugelers et al. (2004)</a> identified a 307C-T transition in the PRKAR1A gene, resulting in an arg74-to-cys (R74C) substitution. The mutation did not result in haploinsufficiency, and lymphoblasts from the proband showed no alteration in R1-alpha protein levels. The phenotypes in affected individuals were typical of Carney complex and included spotty pigmentation, cardiac myxoma, thyroid adenoma, breast myxofibroma, and pulmonic stenosis. One affected member had congenital unilateral deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15371594" 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 in vitro functional expression studies, <a href="#15" class="mim-tip-reference" title="Greene, E. L., Horvath, A. D., Nesterova, M., Giatzakis, C., Bossis, I., Stratakis, C. A. <strong>In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay.</strong> Hum. Mutat. 29: 633-639, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18241045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18241045</a>] [<a href="https://doi.org/10.1002/humu.20688" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18241045">Greene et al. (2008)</a> found that the R74C mutant protein was expressed and resulted in increased PKA activity, most likely caused by decreased binding of the mutant PRKAR1A to cAMP and/or the catalytic subunit. The R74C substitution is located in the linker region of the protein. The findings indicated that altered PRKAR1A activity, not only haploinsufficiency, is sufficient enough to increase PKA activity, which likely results in tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18241045" 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">rs281864801 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864801;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=rs281864801" 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=rs281864801" 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=RCV000013511 OR RCV001387938 OR RCV002496345 OR RCV003882731" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013511, RCV001387938, RCV002496345, RCV003882731" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013511...</a>
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<p>In 12 unrelated kindreds referred for Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD1; <a href="/entry/610489">610489</a>), <a href="#17" class="mim-tip-reference" title="Groussin, L., Horvath, A., Jullian, E., Boikos, S., Rene-Corail, F., Lefebvre, H., Cephise-Velayoudom, F.-L., Vantyghem, M.-C., Chanson, P., Conte-Devolx, B., Lucas, M., Gentil, A., Malchoff, C. D., Tissier, F., Carney, J. A., Bertagna, X., Stratakis, C. A., Bertherat, J. <strong>A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.</strong> J. Clin. Endocr. Metab. 91: 1943-1949, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16464939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16464939</a>] [<a href="https://doi.org/10.1210/jc.2005-2708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16464939">Groussin et al. (2006)</a> reported a 6-bp polypyrimidine tract deletion extending from positions -7 to -2 in intron 6 of the PRKAR1A gene. Nine of the patients had no family history; in 2, there was a family history of isolated PPNAD. Only 1 patient met the criteria for Carney complex (CNC1; <a href="/entry/160980">160980</a>). Some relatives carrying the same mutation had no manifestations of Carney complex or PPNAD, suggesting a low penetrance of this PRKAR1A defect. <a href="#18" class="mim-tip-reference" title="Groussin, L., Jullian, E., Perlemoine, K., Louvel, A., Leheup, B., Luton, J. P., Bertagna, X., Bertherat, J. <strong>Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease.</strong> J. Clin. Endocr. Metab. 87: 4324-4329, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213893</a>] [<a href="https://doi.org/10.1210/jc.2002-020592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213893">Groussin et al. (2002)</a> originally described this mutation in 1 of 5 patients with PPNAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16464939+12213893" 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">rs387906692 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906692;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=rs387906692" 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=rs387906692" 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=RCV000022791 OR RCV000760318 OR RCV001824573 OR RCV001852002 OR RCV003398560" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022791, RCV000760318, RCV001824573, RCV001852002, RCV003398560" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022791...</a>
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<p>In 3 unrelated patients with acrodysostosis-1 with hormone resistance (ACRDYS1; <a href="/entry/101800">101800</a>), <a href="#30" class="mim-tip-reference" title="Linglart, A., Menguy, C., Couvineau, A., Auzan, C., Gunes, Y., Cancel, M., Motte, E., Pinto, G., Chanson, P., Bougneres, P., Clauser, E., Silve, C. <strong>Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance.</strong> New Eng. J. Med. 364: 2218-2226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21651393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21651393</a>] [<a href="https://doi.org/10.1056/NEJMoa1012717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21651393">Linglart et al. (2011)</a> identified a de novo heterozygous 1101C-T transition in exon 11 of the PRKAR1A gene, resulting in an arg368-to-ter (R368X) substitution predicted to result in absence of the cAMP-binding domain B. The mutation was not found in 200 control samples. Patient cells showed decreased protein kinase A activity compared to controls. In vitro functional expression studies showed that the mutant protein had decreased cAMP-induced activation of protein kinase A compared to wildtype. Bioluminescent studies showed that the mutant regulatory PRKAR1A subunits were able to bind protein kinase A catalytic subunits, but were insensitive to dissociation in response to cAMP. Finally, 3-dimensional models indicated that the R368X mutation would lead to abnormalities in the domain B pocket that would preclude high-affinity binding of cAMP. <a href="#30" class="mim-tip-reference" title="Linglart, A., Menguy, C., Couvineau, A., Auzan, C., Gunes, Y., Cancel, M., Motte, E., Pinto, G., Chanson, P., Bougneres, P., Clauser, E., Silve, C. <strong>Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance.</strong> New Eng. J. Med. 364: 2218-2226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21651393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21651393</a>] [<a href="https://doi.org/10.1056/NEJMoa1012717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21651393">Linglart et al. (2011)</a> concluded that this was a gain-of-function mutation that decreased protein kinase A sensitivity to cAMP. The 3 patients had short stature, peripheral dysostosis, nasal and maxillary hypoplasia, severe brachydactyly, epiphyseal stippling, and advanced bone age. Serum parathyroid hormone was markedly increased, but calcium was normal. All had evidence of multiple hormone resistance, including thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. <a href="#30" class="mim-tip-reference" title="Linglart, A., Menguy, C., Couvineau, A., Auzan, C., Gunes, Y., Cancel, M., Motte, E., Pinto, G., Chanson, P., Bougneres, P., Clauser, E., Silve, C. <strong>Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance.</strong> New Eng. J. Med. 364: 2218-2226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21651393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21651393</a>] [<a href="https://doi.org/10.1056/NEJMoa1012717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21651393">Linglart et al. (2011)</a> stated that the mutation resulted in an impairment of protein kinase A activity, not total absence, which may have resulted in variation in the extent to hormone resistance depending on cell-specific expression of alternative protein kinase A isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21651393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Michot, C., Le Goff, C., Goldenberg, A., Abhyankar, A., Klein, C., Kinning, E., Guerrot, A.-M., Flahaut, P., Duncombe, A., Baujat, G., Lyonnet, S., Thalassinos, C., Nitschke, P., Casanova, J.-L., Le Merrer, M., Munnich, A., Cormier-Daire, V. <strong>Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.</strong> Am. J. Hum. Genet. 90: 740-745, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464250</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464250">Michot et al. (2012)</a> identified a heterozygous de novo R368X mutation in 4 unrelated patients with acrodysostosis with hormone resistance. The patients had short stature, severe brachydactyly, short metatarsals, metacarpals, and phalanges, and cone-shaped epiphyses in childhood. Only 2 had mild facial dysostosis and all had normal intellect. All had evidence of hormone resistance, with increased PTH and TSH and clinical hypothyroidism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22464250" 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">rs387906693 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906693;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=rs387906693" 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=rs387906693" 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=RCV000022792 OR RCV002513177" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022792, RCV002513177" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022792...</a>
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<p>In a 22-year-old woman with acrodysostosis-1 with hormone resistance (ACRDYS1; <a href="/entry/101800">101800</a>), <a href="#31" class="mim-tip-reference" title="Michot, C., Le Goff, C., Goldenberg, A., Abhyankar, A., Klein, C., Kinning, E., Guerrot, A.-M., Flahaut, P., Duncombe, A., Baujat, G., Lyonnet, S., Thalassinos, C., Nitschke, P., Casanova, J.-L., Le Merrer, M., Munnich, A., Cormier-Daire, V. <strong>Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.</strong> Am. J. Hum. Genet. 90: 740-745, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464250</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464250">Michot et al. (2012)</a> identified a de novo heterozygous 1117T-C transition in the PRKAR1A gene, resulting in a tyr373-to-his (Y373H) substitution in a highly conserved residue in the catalytic domain. The mutation was not found in 200 controls and was predicted to be damaging by PolyPhen. She had intrauterine growth retardation, short stature, severe brachydactyly, short metatarsals, metacarpals, and phalanges, and cone-shaped epiphyses in childhood. There was evidence of multiple hormone resistance, with increased PTH and TSH and clinical hypothyroidism. She did not have facial dysostosis or intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22464250" 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">rs387906694 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906694;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=rs387906694" 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=rs387906694" 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=RCV000022793" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022793" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022793</a>
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<p>In a patient with acrodysostosis-1 (ACRDYS1; <a href="/entry/101800">101800</a>), <a href="#27" class="mim-tip-reference" title="Lee, H., Graham, J. M., Jr., Rimoin, D. L., Lachman, R. S., Krejci, P., Tompson, S. W., Nelson, S. F., Krakow, D., Cohn, D. H. <strong>Exome sequencing identifies PDE4D mutations in acrodysostosis.</strong> Am. J. Hum. Genet. 90: 746-751, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464252">Lee et al. (2012)</a> identified a de novo heterozygous 1004G-C transversion in exon 11 of the PRKAR1A gene, resulting in an arg335-to-pro (R335P) substitution in the highly conserved cAMP-binding domain B. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. <a href="#27" class="mim-tip-reference" title="Lee, H., Graham, J. M., Jr., Rimoin, D. L., Lachman, R. S., Krejci, P., Tompson, S. W., Nelson, S. F., Krakow, D., Cohn, D. H. <strong>Exome sequencing identifies PDE4D mutations in acrodysostosis.</strong> Am. J. Hum. Genet. 90: 746-751, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464252">Lee et al. (2012)</a> suggested that the mutation would cause reduced cAMP binding, reduced PKA activation, and decreased downstream signaling. The patient had mild short stature, small hands, midface hypoplasia, lumbar stenosis, and mild developmental disability. There was no evidence of endocrine dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22464252" 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>.0018 ACRODYSOSTOSIS 1 WITH HORMONE RESISTANCE</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">rs387906695 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906695;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=rs387906695" 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=rs387906695" 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=RCV000022794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022794</a>
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<p>In a patient with acrodysostosis-1 (ACRDYS1; <a href="/entry/101800">101800</a>), <a href="#27" class="mim-tip-reference" title="Lee, H., Graham, J. M., Jr., Rimoin, D. L., Lachman, R. S., Krejci, P., Tompson, S. W., Nelson, S. F., Krakow, D., Cohn, D. H. <strong>Exome sequencing identifies PDE4D mutations in acrodysostosis.</strong> Am. J. Hum. Genet. 90: 746-751, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464252">Lee et al. (2012)</a> identified a de novo heterozygous 980T-C transition in exon 11 of the PRKAR1A gene, resulting in an ile327-to-thr (I327T) substitution in the highly conserved cAMP-binding domain B. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. <a href="#27" class="mim-tip-reference" title="Lee, H., Graham, J. M., Jr., Rimoin, D. L., Lachman, R. S., Krejci, P., Tompson, S. W., Nelson, S. F., Krakow, D., Cohn, D. H. <strong>Exome sequencing identifies PDE4D mutations in acrodysostosis.</strong> Am. J. Hum. Genet. 90: 746-751, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464252">Lee et al. (2012)</a> suggested that the mutation would cause reduced cAMP binding, reduced PKA activation, and decreased downstream signaling. The patient, previously reported by <a href="#14" class="mim-tip-reference" title="Graham, J. M., Jr., Krakow, D., Tolo, V. T., Smith, A. K., Lachman, R. S. <strong>Radiographic findings and Gs-alpha bioactivity studies and mutation screening in acrodysostosis indicate a different etiology from pseudohypoparathyroidism.</strong> Pediat. Radiol. 31: 2-9, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11200992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11200992</a>] [<a href="https://doi.org/10.1007/s002470000355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11200992">Graham et al. (2001)</a> (case 1), had mild short stature, small hands, midface hypoplasia, lumbar stenosis, and mild developmental disability. He had congenital hypothyroidism, unilateral undescended testes, and moderate mixed hearing loss. Other features included dextrocardia, Kartagener syndrome (<a href="/entry/244400">244400</a>), and multiple orthopedic problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11200992+22464252" 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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Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Ranganath, S., Li, G., Schrum, J. P., Manis, J. P., Alt, F. W.
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[<a href="https://doi.org/10.1093/hmg/9.20.3037" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(02)09966-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.03.004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.85.19.7302" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1012717" target="_blank">Full Text</a>]
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<strong>Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464250</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22464250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.03.003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg160" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-0188" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0006-291x(87)90499-2" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12203783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12203783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12203783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/gcc.10112" target="_blank">Full Text</a>]
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<a id="Schernthaner-Reiter2018" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1093/hmg/ddy166" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0405535101" target="_blank">Full Text</a>]
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Zhang, J., Hupfeld, C. J., Taylor, S. S., Olefsky, J. M., Tsien, R. Y.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177793" 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/nature04140" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
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Bao Lige - updated : 02/25/2020
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 5/1/2012<br>George E. Tiller - updated : 11/17/2011<br>Cassandra L. Kniffin - updated : 7/11/2011<br>Carol A. Bocchini - updated : 6/3/2009<br>Cassandra L. Kniffin - updated : 8/25/2008<br>Cassandra L. Kniffin - updated : 4/21/2008<br>John A. Phillips, III - updated : 7/18/2007<br>John A. Phillips, III - updated : 7/16/2007<br>Ada Hamosh - updated : 1/30/2006<br>Ada Hamosh - updated : 11/3/2005<br>George E. Tiller - updated : 4/22/2005<br>Ada Hamosh - updated : 3/3/2005<br>Ada Hamosh - updated : 2/25/2005<br>Cassandra L. Kniffin - updated : 1/24/2005<br>Victor A. McKusick - updated : 12/2/2004<br>Victor A. McKusick - updated : 11/26/2003<br>Victor A. McKusick - updated : 1/8/2003<br>John A. Phillips, III - updated : 12/16/2002<br>Victor A. McKusick - updated : 11/11/2002<br>Paul J. Converse - updated : 5/4/2001<br>George E. Tiller - updated : 3/5/2001<br>Anne M. Stumpf - updated : 2/14/2001<br>Victor A. McKusick - updated : 8/29/2000<br>Victor A. McKusick - updated : 8/28/2000
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/16/1986
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/29/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/28/2024<br>mgross : 02/25/2020<br>mgross : 02/25/2020<br>carol : 04/29/2019<br>alopez : 04/24/2019<br>alopez : 02/01/2018<br>joanna : 08/04/2016<br>alopez : 08/31/2015<br>carol : 3/5/2014<br>alopez : 1/29/2014<br>carol : 9/17/2013<br>terry : 9/14/2012<br>terry : 5/4/2012<br>carol : 5/4/2012<br>ckniffin : 5/1/2012<br>terry : 2/16/2012<br>terry : 1/17/2012<br>carol : 11/22/2011<br>terry : 11/17/2011<br>wwang : 7/13/2011<br>ckniffin : 7/11/2011<br>carol : 9/17/2009<br>terry : 6/4/2009<br>carol : 6/3/2009<br>carol : 10/9/2008<br>wwang : 9/18/2008<br>ckniffin : 8/25/2008<br>wwang : 4/23/2008<br>ckniffin : 4/21/2008<br>alopez : 3/25/2008<br>carol : 2/15/2008<br>carol : 1/31/2008<br>carol : 1/2/2008<br>alopez : 7/18/2007<br>alopez : 7/16/2007<br>carol : 10/18/2006<br>ckniffin : 10/17/2006<br>carol : 4/17/2006<br>alopez : 1/31/2006<br>terry : 1/30/2006<br>alopez : 11/7/2005<br>alopez : 11/7/2005<br>terry : 11/3/2005<br>tkritzer : 4/22/2005<br>alopez : 3/4/2005<br>terry : 3/3/2005<br>wwang : 3/3/2005<br>wwang : 3/3/2005<br>wwang : 2/28/2005<br>terry : 2/25/2005<br>tkritzer : 1/27/2005<br>ckniffin : 1/24/2005<br>tkritzer : 12/9/2004<br>terry : 12/2/2004<br>terry : 2/23/2004<br>tkritzer : 12/8/2003<br>tkritzer : 12/4/2003<br>terry : 11/26/2003<br>tkritzer : 1/16/2003<br>tkritzer : 1/9/2003<br>terry : 1/8/2003<br>alopez : 12/16/2002<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>mgross : 5/4/2001<br>cwells : 3/6/2001<br>cwells : 3/5/2001<br>cwells : 3/2/2001<br>carol : 2/14/2001<br>alopez : 2/14/2001<br>alopez : 8/30/2000<br>terry : 8/29/2000<br>terry : 8/28/2000<br>alopez : 10/19/1998<br>dkim : 9/22/1998<br>mark : 3/24/1997<br>terry : 9/6/1996<br>terry : 9/5/1996<br>carol : 3/18/1993<br>carol : 10/12/1992<br>carol : 7/7/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 188830
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE I, ALPHA; PRKAR1A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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PROTEIN KINASE A, RI-ALPHA SUBUNIT<br />
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TISSUE-SPECIFIC EXTINGUISHER 1; TSE1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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PRKAR1A/RARA FUSION GENE, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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PTC2 CHIMERIC ONCOGENE, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PRKAR1A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 17q24.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:68,413,623-68,551,316 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
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<span class="mim-font">
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17q24.2
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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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Acrodysostosis 1, with or without hormone resistance
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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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101800
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Adrenocortical tumor, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Carney complex, type 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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160980
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Myxoma, intracardiac
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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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255960
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Pigmented nodular adrenocortical disease, primary, 1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
610489
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>PRKAR1A is a critical component of type I protein kinase A (PKA), the main mediator of cAMP signaling in mammals. PKA is a tetramer consisting of 2 regulatory and 2 catalytic subunits. It is inactive in the absence of cAMP. Activation occurs when 2 cAMP molecules bind to each regulatory subunit, eliciting a reversible conformational change that releases active catalytic subunits. Four distinct regulatory subunits of PKA have been identified: RI-alpha, RI-beta (176911), RII-alpha (176910), and RII-beta (176912). Phosphorylation mediated by the cAMP/PKA signaling pathway is involved in the regulation of metabolism, cell proliferation, differentiation, and apoptosis (review by Bossis and Stratakis, 2004). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Extinction is an operational term that refers to the lack of expression of tissue-specific traits and is generally observed in hybrid cells formed by fusing dissimilar cell types. Killary and Fournier (1984) studied extinction of liver-specific tyrosine aminotransferase (613018) when rat hepatoma cells were fused with mouse fibroblasts. By microcell hybrids, they showed that mouse chromosome 11 was specifically responsible for extinction and that homologous human chromosome 17 had the same activity. The tissue-specific extinguisher-1 locus (Tse1) in the mouse represses gene expression in trans. To search for other Tse1-responsive genes, Lem et al. (1988) screened for expression of liver-specific mRNAs in hepatoma microcell hybrids containing mouse chromosome 11 or human chromosome 17. Whereas most liver gene activity was unaffected in such hybrids, phosphoenolpyruvate carboxykinase (261650, 261680) and tyrosine aminotransferase gene expression was coordinately repressed in these clones. Extinction of both genes was apparently mediated by a single genetic locus that resides on human chromosome 17. </p><p>Sandberg et al. (1987) cloned the regulatory subunit of type I cAMP-dependent protein kinase A from a human testis cDNA library. The cDNA encodes a deduced 381-amino acid protein. Northern blot analysis demonstrated 1.5- and 3.0-kb mRNA transcripts in human testis and a 3.0-kb transcript in human T lymphocytes. </p><p>Boshart et al. (1991) identified the regulatory subunit RI-alpha of PKA as the product of the TSE1 locus. The evidence consisted of concordant expression of RI-alpha mRNA and TSE1 genetic activity, high resolution physical mapping of the 2 genes on human chromosome 17, and the ability of transfected RI-alpha cDNA to generate a phenocopy of TSE1-mediated extinction. Jones et al. (1991) independently established identity of TSE1 and the RI-alpha subunit. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Catalano et al. (2007) noted that the PRKAR1A gene maps to chromosome 17q24. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Amieux et al. (2002) presented evidence indicating that increased basal PKA activity resulting from targeted disruption of the mouse RI-alpha isoform affects signaling in the primitive streak, causing profound deficits in the production of all mesoderm derivatives including the heart. In contrast, disruption of the RII-alpha subunit did not result in any developmental defects. </p><p>Jia et al. (2004) showed that PKA and casein kinase I (CKI; 600505) regulate Smo (601500) cell surface accumulation and activity in response to hedgehog (Hh; see 600725). Blocking PKA or CKI activity in the Drosophila wing disc prevented Hh-induced Smo accumulation and attenuated pathway activity, whereas increasing PKA activity promoted Smo accumulation and pathway activation. Jia et al. (2004) showed that PKA and CKI phosphorylate Smo at several sites, and that phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal. Conversely, phosphorylation-mimicking Smo variants showed constitutive cell surface expression and signaling activity. Furthermore, Jia et al. (2004) found that the levels of Smo cell surface expression and activity correlated with its levels of phosphorylation. Jia et al. (2004) concluded that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell surface levels and signaling activity. </p><p>Using immunofluorescent and confocal microscopy, Durick et al. (1998) demonstrated that ENIGMA (605903) is localized through its PDZ domain to the cell periphery and in some cytoskeletal components, and that ENIGMA colocalizes with RET/PTC2. Yeast 2-hybrid analysis showed that ENIGMA binds through its LIM2 domain to RET/PTC2 at tyr586 in a phosphorylation-independent manner, and that this interaction, as well as binding by SHC1 (600560), is required for RET/PTC2 mitogenic activity. </p><p>Zhang et al. (2005) showed that in adipocytes, chronically high insulin levels inhibit beta-adrenergic receptors (see 109630), but not other cAMP-elevating stimuli, from activating PKA. They measured this using an improved fluorescent reporter and by phosphorylation of endogenous CREB (123810). Disruption of PKA scaffolding mimicked the interference of insulin with beta-adrenergic receptor signaling. Zhang et al. (2005) suggested that chronically high insulin levels may disrupt the close apposition of beta-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways. </p><p>Dodge-Kafka et al. (2005) identified a cAMP-responsive signaling complex maintained by the muscle-specific A-kinase anchoring protein (AKAP6; 604691) that includes PKA, PDE4D3 (600129), and EPAC1 (606057). These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an AKAP6-associated ERK5 (602521) kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits EPAC1, an exchange factor for the small GTPase RAP1 (179520), to enable cAMP-dependent attenuation of ERK5. Pharmacologic and molecular manipulations of the AKAP6 complex showed that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, Dodge-Kafka et al. (2005) concluded that 2 coupled cAMP-dependent feedback loops are coordinated within the context of the AKAP6 complex, suggesting that local control of cAMP signaling by AKAP proteins is more intricate than had been appreciated. </p><p>Using a combination of in vitro explant assays, mutant analysis, and gene delivery into mouse embryos cultured ex vivo, Chen et al. (2005) demonstrated that adenylyl cyclase (see 103072) signaling through PKA and its target transcription factor CREB are required for Wnt (see 164820)-directed myogenic gene expression. Wnt proteins can also stimulate CREB-mediated transcription, providing evidence for a Wnt signaling pathway involving PKA and CREB. </p><p>Basu et al. (2005) showed that activation-induced cytidine deaminase (AID; 605257) from B cells is phosphorylated on a consensus PKA site and that PKA is the physiologic AID kinase. Basu et al. (2005) showed that AID from nonlymphoid cells can be functionally phosphorylated by recombinant PKA to allow interaction with replication protein A (RPA; see 179835) and promote deamination of transcribed double-stranded DNA (dsDNA) substrates. Moreover, mutation of the major PKA phosphorylation site of AID preserves single-stranded DNA (ssDNA) deamination activity, but markedly reduces RPA-dependent dsDNA deamination activity and severely impairs the ability of AID to effect class switch recombination in vivo. Basu et al. (2005) concluded that PKA has a critical role in posttranslational regulation of AID activity in B cells. </p><p>Schernthaner-Reiter et al. (2018) found that endogenous Aip (605555) physically interacted and colocalized with R1-alpha and C-alpha (PRKACA; 601639) in the cytoplasm of rat mammosomatotropinoma cell line GH3. Fractionation analysis showed that all 3 proteins localized to cytoplasm and membranes of GH3 cells. Aip interacted with R1-alpha and C-alpha separately and in a 3-protein complex. Aip overexpression reduced PKA activity in GH3 cells. C-alpha overexpression stabilized both Aip and R1-alpha protein levels independent of PKA activity. Aip protein level was regulated by translation and degradation via the ubiquitin/proteasome pathway. Aip knockdown modestly increased PKA activity in GH3 cells. Further analysis revealed that Aip functionally interacted with PDE-dependent PKA pathway activity via Pde4 (600126). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kim et al. (2005) determined the crystal structure of the cAMP-dependent protein kinase catalytic subunit bound to a deletion mutant of the regulatory subunit (RI-alpha) at 2.0-angstrom resolution. This structure defines a previously unidentified extended interface in which the large lobe of the catalytic subunit is like a stable scaffold where tyr247 in the G helix and trp196 in the phosphorylated activation loop serve as anchor points for binding the RI-alpha subunit. These residues compete with cAMP for the phosphate-binding cassette in RI-alpha. In contrast to this catalytic subunit, RI-alpha undergoes major conformational changes when the complex is compared with cAMP-bound RI-alpha. Kim et al. (2005) concluded that the complex provides a molecular mechanism for inhibition of PKA and suggests how cAMP binding leads to activation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Papillary thyroid carcinoma (see 188550) can be caused by chimeric oncogenes formed by fusion of the tyrosine kinase domain of the RET protooncogene (164761) to the 5-prime terminal region of another gene. See, for example, PTC1 (601985). Bongarzone et al. (1993) isolated and sequenced a type of RET oncogenic rearrangement involving the TSE1 gene. Analysis of the nucleotide sequence indicated that the transforming activity was created by the fusion of the RET tyrosine kinase domain with part of the RI-alpha regulatory subunit of PKA. The authors stated that this was the first example of an oncogenic activity involving a PKA gene. The chimeric oncogene formed by the fusion of the RET and TSE1 genes is known as PTC2. </p><p>Catalano et al. (2007) reported a 66-year-old man with acute promyelocytic leukemia (APL) who was found to have a PRKAR1A/RARA (180240) fusion gene, possibly resulting from an insertion of RARA distal to PRKAR1A, followed by a deletion of 3-prime PRKAR1A, 5-prime RARA, and any intervening sequences. The fusion transcript resulted from cryptic splicing of the first 100 bases of PRKAR1A exon 3 to the 5-prime end of RARA exon 3, and predicted a 495-amino acid fusion protein. The C-terminal end of RARA involved is that shared by all RARA rearrangements in APL. The patient had a good response to chemotherapy with complete remission of the disease by 11 months. Catalano et al. (2007) postulated that fusion of the R1-alpha dimerization domain to RARA may be involved in deregulation of PKA. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Carney Complex Type 1</em></strong></p><p>
|
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Carney complex (see CNC1, 160980) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas. Because of its similarities to the McCune-Albright syndrome (MAS; 174800) and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signaling were thought to be candidates for the site of mutation(s) in Carney complex (DeMarco et al., 1996). In tumor tissue from Carney complex families mapping to 17q, Kirschner et al. (2000) detected loss of heterozygosity (LOH) in the vicinity of the PRKAR1A gene, including a polymorphic site within its 5-prime region. In affected members of 3 unrelated kindreds, they identified a germline mutation in the PRKAR1A gene (188830.0001). Analysis of additional cases demonstrated the same mutation in a sporadic case of Carney complex, and different mutations in 3 other families, including 1 with isolated inherited cardiac myxomas (188830.0002-188830.0004). Analysis of protein kinase A (PKA) activity in Carney complex tumors demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-Carney complex tumors. Kirschner et al. (2000) concluded that germline mutations in PRKAR1A, an apparent tumor-suppressor gene, are responsible for the Carney complex phenotype in a subset of patients with that disorder. </p><p>Independently, Casey et al. (2000) had noted from a search of the Human Genome Project databases that the PRKAR1A gene is included within the minimal interval for the Carney complex locus on 17q. Furthermore, they noted that a human genomic BAC clone contained sequences corresponding to both PRKAR1A and an anonymous marker that exhibited no recombination with the Carney complex gene in families they had studied. Therefore, the PRKAR1A chromosomal location, the known role of PKA in signal transduction and cell growth, and the ubiquitous expression pattern of the R1-alpha subunit all suggested this gene as a candidate for Carney complex. In affected members of 3 unrelated families, they demonstrated PRKAR1A frameshift mutations resulting in haploinsufficiency of R1-alpha (188830.0005-188830.0007). </p><p>Kirschner et al. (2000) identified the PRKAR1A genomic structure, screened for mutations in 34 CNC families and 20 patients with sporadic disease, and confirmed the genetic heterogeneity of CNC. Altogether, 15 distinct PRKAR1A mutations were identified in 22 (41%) of 54 kindreds. In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay (NMD). Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. The authors concluded that all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. Six families mapped to the CNC2 locus (605244) on 2p16. </p><p>Robinson-White et al. (2003) determined that PKA activity both at baseline and after stimulation with cAMP was augmented in cells carrying PRKAR1A mutations. Quantitative message analysis showed that the main PKA subunits expressed were type I (RI-alpha and RI-beta), but RI-alpha was decreased in mutant cells. Immunoblot assays of ERK1/2 (601795, 176948) phosphorylation by the cell- and pathway-specific stimulant lysophosphatidic acid (LPA) showed activation of this pathway in a time- and concentration-dependent manner that was prevented by a specific inhibitor. There was a greater rate of growth in mutant cells; forskolin and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal but not in mutant cells. Forskolin inhibited LPA-induced cell proliferation and metabolism in normal cells, but stimulated these parameters in mutant cells. These data were also replicated in a pituitary tumor cell line carrying the most common PRKAR1A mutation, 578delTG (188830.0001), and an in vitro construct of mutant PRKAR1A that was shown to lead to augmented PKA-mediated phosphorylation. Robinson-White et al. (2003) concluded that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism, and proliferation. They speculated that reversal of PKA-mediated inhibition of this MAPK pathway in CNC cells may contribute to tumorigenesis in this condition. </p><p>Robinson-White et al. (2006) investigated how PKA and its subunits and ERK1/2 and their molecular partners change in the presence of PRKAR1A mutations in adrenocortical tissue. Mutations in PRKAR1A caused increased total cAMP-stimulated kinase activity, likely the result of upregulation of other PKA subunits caused by downregulation of RI-alpha, as seen in human lymphocytes and mouse animal models. The authors concluded that these changes, associated with enhanced MAPK activity, may be, in part, responsible for the proliferative signals that result in primary pigmented nodular adrenocortical disease. </p><p>Veugelers et al. (2004) performed mutation analysis of the PRKAR1A gene in 51 unrelated probands with Carney complex and identified mutations in 33 (65%). All mutations, except for 1 missense mutation (188830.0013), led to PRKAR1A haploinsufficiency. </p><p>Greene et al. (2008) identified 7 pathogenic PRKAR1A mutations (see, e.g., 188830.0013) that resulted in expressed mutant proteins and not premature stop codons that lead to subsequent NMD. In vitro functional expression studies showed that the mutant proteins all resulted in increased PKA activity, most likely caused by decreased binding of the mutant PRKAR1A to cAMP and/or the catalytic subunit. The findings suggested that altered PRKAR1A activity, not only haploinsufficiency, is sufficient enough to increase PKA activity, which likely results in tumorigenesis. </p><p><strong><em>Primary Pigmented Nodular Adrenocortical Disease 1</em></strong></p><p>
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|
Groussin et al. (2002) studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD1; 601489) or Carney complex and found that 9 of them had PRKAR1A gene defects (including 7 novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, in 1 kindred, a splice site mutation, IVS6+1G-T (188830.0011), led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear level. The authors stated that this was the first demonstration of an inactivating PRKAR1A mutation expressed at the protein level and leading to stimulation of the PKA pathway in patients with Carney complex. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis in tissues in patients with Carney complex. </p><p><strong><em>Acrodysostosis 1</em></strong></p><p>
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|
In 3 unrelated patients with acrodysostosis with hormone resistance (ACRDYS1; 101800), Linglart et al. (2011) identified a de novo truncating mutation in the PRKAR1A gene (R368X; 188830.0015). The mutation resulted in decreased protein kinase A sensitivity to cAMP, causing multiple hormone resistance and skeletal anomalies. </p><p><strong><em>Systemic Lupus Erythematosus</em></strong></p><p>
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Systemic lupus erythematosus (SLE; 152700) is an autoimmune disorder characterized by diverse dysfunctions of immune effector cells, including proliferation and cytotoxicity. In T cells from patients with SLE, activity of type 1 protein kinase A isozymes is greatly reduced because of decreased expression of the alpha and beta regulatory subunits. Laxminarayana et al. (2002) cloned and sequenced cDNA of PRKAR1A and corresponding genomic DNA of the coding region to detect sequence changes from 8 patients with SLE and 6 healthy controls. Various transcript mutations, including deletions, transitions, and transversions, were found at a frequency 7.5 times higher than that in control T cells. By contrast, no genomic mutations were identified. Because transcript editing is regulated by adenosine deaminases that act on RNA (ADAR; 146920), they quantified expression of ADAR1 transcripts in SLE and control cells, finding that ADAR1 mRNA content was 3.5 times higher in SLE cells than in control T cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Because they had identified 24 mutations in the PRKAR1A gene in 33 of 51 (65%) unrelated probands with Carney complex, all but 1 of which resulted in haploinsufficiency, Veugelers et al. (2004) studied the consequences of Prkar1a haploinsufficiency in mice. Although they did not observe cardiac myxomas or altered pigmentation in Prkar1a +/- mice, they did observe some phenotypes similar to Carney complex, including altered heart rate variability. Moreover, Prkar1a +/- mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from Prkar1a +/- mice did not exhibit Prkar1a loss of heterozygosity. Veugelers et al. (2004) concluded that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation. </p><p>Griffin et al. (2004) created a transgenic mouse model carrying an antisense transgene for Prkar1a, resulting in an approximately 50% decrease in protein levels similar to haploinsufficiency. The transgenic mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, hypercorticosteronemia, late-onset weight gain, visceral adiposity, and mesenchymal tumors. The thyroid and adrenocortical tumors showed loss of heterozygosity at the Prkar1a locus. Griffin et al. (2004) suggested that the transgenic mice displayed several findings seen in patients with Carney complex, supporting the role of PRKAR1A as a tumor suppressor gene. </p><p>Almeida et al. (2010) investigated Prkar1a +/- mice when bred within the Rb1 +/- (614041) or Trp53 +/- (191170) backgrounds, or treated with a 2-step skin carcinogenesis protocol. Prkar1a +/- Trp53 +/- mice developed more sarcomas than Trp53 +/- mice (p less than 0.05), and Prkar1a +/- Rb1 +/- mice grew more (and larger) pituitary and thyroid tumors than Rb1 +/- mice. All mice with double heterozygosity had significantly reduced life spans compared with their single-heterozygous counterparts. Prkar1a +/- mice also developed more papillomas than wildtype animals. A whole-genome transcriptome profiling of tumors produced by all 3 models identified Wnt signaling as the main pathway activated by abnormal cAMP signaling, along with cell cycle abnormalities. siRNA downregulation of Ctnnb1 (116806), E2f1 (189971), or Cdk4 (123829) inhibited proliferation of human adrenal cells bearing a PRKAR1A-inactivating mutation and Prkar1a +/- mouse embryonic fibroblasts and arrested both cell lines at the G0/G1 phase of the cell cycle. Almeida et al. (2010) concluded that Prkar1a haploinsufficiency is a relatively weak tumorigenic signal that can act synergistically with other tumor suppressor gene defects or chemicals to induce tumors, mostly through Wnt-signaling activation and cell cycle dysregulation. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>18 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, 2-BP DEL, 578TG
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<br />
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SNP: rs281864790,
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ClinVar: RCV000013498, RCV000414608, RCV002345241
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 unrelated families with Carney complex (CNC1; 160980), Kirschner et al. (2000) identified a heterozygous 2-bp deletion (578delTG) in exon 4B of the PRKAR1A gene, resulting in a frameshift and premature termination of the protein before the cAMP binding domain. The families did not share the same chromosome 17 haplotype on the disease-bearing allele. The 2-bp deletion was also found in a third family and in a sporadic case. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, 889GG-CT
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<br />
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SNP: rs281864785,
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ClinVar: RCV000013499
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; 160980), Kirschner et al. (2000) identified a heterozygous 889GG-CT change in exon 8 of the PRKAR1A gene, leading to premature termination after residue 204 and truncation of the N terminus at the second cAMP binding 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>.0003 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, IVS8DS, A-G, +3
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<br />
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SNP: rs281864799,
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ClinVar: RCV000013500, RCV001857341, RCV004649063
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; 160980), Kirschner et al. (2000) identified a heterozygous A-to-G transition at position +3 of intron 8 of the PRKAR1A gene, presumably resulting in a defect in splicing of the protein product. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MYXOMA, INTRACARDIAC</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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PRKAR1A, 4-BP DEL, 617TTAT
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<br />
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SNP: rs281864791,
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ClinVar: RCV000013501
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family segregating cardiac myxomas (255960) and no other features of Carney complex (CNC1; 160980), originally reported by Liebler et al. (1976), Kirschner et al. (2000) identified a heterozygous 4-bp deletion, 617TTAT, in exon 5 of the PRKAR1A gene. The deletion resulted in a frameshift after residue 204 and a stop codon after 26 missense residues. The mutation would abolish the second cAMP-binding 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>.0005 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, 1-BP DEL, 710G
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<br />
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SNP: rs727503379,
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ClinVar: RCV000151681, RCV000317950, RCV001382880
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; 160980), Casey et al. (2000) demonstrated a 1-bp deletion (G) at nucleotide 710 of the PRKAR1A gene (gly208 of the protein), with a consequent frameshift and premature stop 13 codons later. </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>.0006 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, 2-BP DEL, 845TC
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<br />
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|
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ClinVar: RCV000013503, RCV003298031
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; 160980), Casey et al. (2000) found a 2-bp deletion (TC) of nucleotides 845-846 at val253 of the PRKAR1A gene, with a consequent frameshift and a premature stop 15 codons later. </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>.0007 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, 2-BP DEL, 576TG
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<br />
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ClinVar: RCV000013498, RCV000414608, RCV002345241
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Carney complex (CNC1; 160980), Casey et al. (2000) found a 2-bp deletion (TG) of nucleotides 576-577 at thr163 of the PRKAR1A gene, resulting in a frameshift and a premature stop 6 codons later. </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>.0008 CARNEY COMPLEX, TYPE 1</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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PRKAR1A, 88AG
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<br />
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SNP: rs281864779,
|
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|
|
|
|
ClinVar: RCV000013505, RCV000523178
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|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family with Carney complex (CNC1; 160980), Kirschner et al. (2000) found an A-to-G transition at nucleotide 88 of the PRKAR1A gene, abolishing the ATG translation start codon in exon 2. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1</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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PRKAR1A, 102G-A
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<br />
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SNP: rs587776773,
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|
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|
|
|
|
|
ClinVar: RCV000013506, RCV001851827
|
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|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>Groussin et al. (2002) investigated the genetics of patients with sporadic and isolated primary pigmented nodular adrenocortical disease (PPNAD1; 610489) by sequencing the PRKAR1A gene in 5 patients. Different inactivating germline mutations were found in all 5 patients. In an 18-year-old woman of African origin with ACTH-independent Cushing syndrome, who presented with a 2.5-cm macronodule of the right adrenal mimicking an adrenal adenoma, the authors found 2 mutations in the PRKAR1A gene. One was a germline point mutation in the splice donor site of exon 1B, 102G-A, that resulted in partial exon skipping. An abnormally short mRNA was predicted to impede translation into PRKAR1A protein. The second mutation was a 16-bp deletion of the acceptor splice site of exon 4B (-17 to -2) that was found only in the macronodule of the right adrenal. Groussin et al. (2002) concluded that inactivating germline mutations of PRKAR1A are frequent in sporadic and isolated cases of PPNAD. The wildtype allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PRKAR1A, 16-BP DEL
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<br />
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ClinVar: RCV000013507
|
|
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|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>See 188830.0009 and Groussin et al. (2002). </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CARNEY COMPLEX, TYPE 1</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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PRKAR1A, IVS6DS, G-T, +1
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<br />
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|
|
SNP: rs281864798,
|
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|
|
ClinVar: RCV000013508
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son with Carney complex (CNC1; 160980), Groussin et al. (2002) demonstrated heterozygosity for a splice site mutation in the PRKAR1A gene, IVS6+1G-T, which led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mother had the disorder in severe form and died of a pancreatic adenocarcinoma with rapidly growing liver metastasis. She had lentigines, heart myxoma, primary pigmented nodular adrenocortical disease, toxic multinodular goiter, and ovarian cyst. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that it activated PKA signaling at the nuclear level. Along with a lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 ADRENOCORTICAL TUMOR, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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PRKAR1A, IVS9AS, G-A, -1
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<br />
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|
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SNP: rs587776774,
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|
|
ClinVar: RCV000013509
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 cases of sporadic adrenocortical tumor, Bertherat et al. (2003) identified somatic mutations in the PRKAR1A gene, 1 of which was a splicing mutation (IVS9AS-1G-A). All 3 mutations predicted premature termination of the protein. Somatic alterations in PRKAR1A had previously been described only in thyroid tumors (Sandrini et al., 2002). </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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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CARNEY COMPLEX, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
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|
|
|
PRKAR1A, ARG74CYS
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<br />
|
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|
|
SNP: rs137853303,
|
|
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|
|
|
gnomAD: rs137853303,
|
|
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|
|
ClinVar: RCV000013510, RCV000148738, RCV001014797, RCV003320547, RCV003407324, RCV003466855
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an English family with Carney complex (CNC1; 160980), Veugelers et al. (2004) identified a 307C-T transition in the PRKAR1A gene, resulting in an arg74-to-cys (R74C) substitution. The mutation did not result in haploinsufficiency, and lymphoblasts from the proband showed no alteration in R1-alpha protein levels. The phenotypes in affected individuals were typical of Carney complex and included spotty pigmentation, cardiac myxoma, thyroid adenoma, breast myxofibroma, and pulmonic stenosis. One affected member had congenital unilateral deafness. </p><p>By in vitro functional expression studies, Greene et al. (2008) found that the R74C mutant protein was expressed and resulted in increased PKA activity, most likely caused by decreased binding of the mutant PRKAR1A to cAMP and/or the catalytic subunit. The R74C substitution is located in the linker region of the protein. The findings indicated that altered PRKAR1A activity, not only haploinsufficiency, is sufficient enough to increase PKA activity, which likely results in tumorigenesis. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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|
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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>.0014 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CARNEY COMPLEX, TYPE I, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRKAR1A, IVS6, 6-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs281864801,
|
|
|
|
|
|
|
|
ClinVar: RCV000013511, RCV001387938, RCV002496345, RCV003882731
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 12 unrelated kindreds referred for Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD1; 610489), Groussin et al. (2006) reported a 6-bp polypyrimidine tract deletion extending from positions -7 to -2 in intron 6 of the PRKAR1A gene. Nine of the patients had no family history; in 2, there was a family history of isolated PPNAD. Only 1 patient met the criteria for Carney complex (CNC1; 160980). Some relatives carrying the same mutation had no manifestations of Carney complex or PPNAD, suggesting a low penetrance of this PRKAR1A defect. Groussin et al. (2002) originally described this mutation in 1 of 5 patients with PPNAD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 ACRODYSOSTOSIS 1 WITH HORMONE RESISTANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRKAR1A, ARG368TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906692,
|
|
|
|
|
|
|
|
ClinVar: RCV000022791, RCV000760318, RCV001824573, RCV001852002, RCV003398560
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated patients with acrodysostosis-1 with hormone resistance (ACRDYS1; 101800), Linglart et al. (2011) identified a de novo heterozygous 1101C-T transition in exon 11 of the PRKAR1A gene, resulting in an arg368-to-ter (R368X) substitution predicted to result in absence of the cAMP-binding domain B. The mutation was not found in 200 control samples. Patient cells showed decreased protein kinase A activity compared to controls. In vitro functional expression studies showed that the mutant protein had decreased cAMP-induced activation of protein kinase A compared to wildtype. Bioluminescent studies showed that the mutant regulatory PRKAR1A subunits were able to bind protein kinase A catalytic subunits, but were insensitive to dissociation in response to cAMP. Finally, 3-dimensional models indicated that the R368X mutation would lead to abnormalities in the domain B pocket that would preclude high-affinity binding of cAMP. Linglart et al. (2011) concluded that this was a gain-of-function mutation that decreased protein kinase A sensitivity to cAMP. The 3 patients had short stature, peripheral dysostosis, nasal and maxillary hypoplasia, severe brachydactyly, epiphyseal stippling, and advanced bone age. Serum parathyroid hormone was markedly increased, but calcium was normal. All had evidence of multiple hormone resistance, including thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. Linglart et al. (2011) stated that the mutation resulted in an impairment of protein kinase A activity, not total absence, which may have resulted in variation in the extent to hormone resistance depending on cell-specific expression of alternative protein kinase A isoforms. </p><p>Michot et al. (2012) identified a heterozygous de novo R368X mutation in 4 unrelated patients with acrodysostosis with hormone resistance. The patients had short stature, severe brachydactyly, short metatarsals, metacarpals, and phalanges, and cone-shaped epiphyses in childhood. Only 2 had mild facial dysostosis and all had normal intellect. All had evidence of hormone resistance, with increased PTH and TSH and clinical hypothyroidism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 ACRODYSOSTOSIS 1 WITH HORMONE RESISTANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRKAR1A, TYR373HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906693,
|
|
|
|
|
|
|
|
ClinVar: RCV000022792, RCV002513177
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 22-year-old woman with acrodysostosis-1 with hormone resistance (ACRDYS1; 101800), Michot et al. (2012) identified a de novo heterozygous 1117T-C transition in the PRKAR1A gene, resulting in a tyr373-to-his (Y373H) substitution in a highly conserved residue in the catalytic domain. The mutation was not found in 200 controls and was predicted to be damaging by PolyPhen. She had intrauterine growth retardation, short stature, severe brachydactyly, short metatarsals, metacarpals, and phalanges, and cone-shaped epiphyses in childhood. There was evidence of multiple hormone resistance, with increased PTH and TSH and clinical hypothyroidism. She did not have facial dysostosis or intellectual disability. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 ACRODYSOSTOSIS 1 WITHOUT HORMONE RESISTANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRKAR1A, ARG335PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906694,
|
|
|
|
|
|
|
|
ClinVar: RCV000022793
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acrodysostosis-1 (ACRDYS1; 101800), Lee et al. (2012) identified a de novo heterozygous 1004G-C transversion in exon 11 of the PRKAR1A gene, resulting in an arg335-to-pro (R335P) substitution in the highly conserved cAMP-binding domain B. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. Lee et al. (2012) suggested that the mutation would cause reduced cAMP binding, reduced PKA activation, and decreased downstream signaling. The patient had mild short stature, small hands, midface hypoplasia, lumbar stenosis, and mild developmental disability. There was no evidence of endocrine dysfunction. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ACRODYSOSTOSIS 1 WITH HORMONE RESISTANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRKAR1A, ILE327THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906695,
|
|
|
|
|
|
|
|
ClinVar: RCV000022794
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acrodysostosis-1 (ACRDYS1; 101800), Lee et al. (2012) identified a de novo heterozygous 980T-C transition in exon 11 of the PRKAR1A gene, resulting in an ile327-to-thr (I327T) substitution in the highly conserved cAMP-binding domain B. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. Lee et al. (2012) suggested that the mutation would cause reduced cAMP binding, reduced PKA activation, and decreased downstream signaling. The patient, previously reported by Graham et al. (2001) (case 1), had mild short stature, small hands, midface hypoplasia, lumbar stenosis, and mild developmental disability. He had congenital hypothyroidism, unilateral undescended testes, and moderate mixed hearing loss. Other features included dextrocardia, Kartagener syndrome (244400), and multiple orthopedic problems. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Almeida, M. Q., Muchow, M., Boikos, S., Bauer, A. J., Griffin, K. J., Tsang, K. M., Cheadle, C., Watkins, T., Wen, F., Starost, M. F., Bossis, I., Nesterova, M., Stratakis, C. A.
|
|
<strong>Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/- or Rb1+/- backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling.</strong>
|
|
Hum. Molec. Genet. 19: 1387-1398, 2010.
|
|
|
|
|
|
[PubMed: 20080939]
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|
|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddq014]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Amieux, P. S., Howe, D. G., Knickerbocker, H., Lee, D. C., Su, T., Laszlo, G. S., Idzerda, R. L., McKnight, G. S.
|
|
<strong>Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo.</strong>
|
|
J. Biol. Chem. 277: 27294-27304, 2002.
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|
|
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|
|
[PubMed: 12004056]
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|
|
[Full Text: https://doi.org/10.1074/jbc.M200302200]
|
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Ranganath, S., Li, G., Schrum, J. P., Manis, J. P., Alt, F. W.
|
|
<strong>The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation.</strong>
|
|
Nature 438: 508-511, 2005.
|
|
|
|
|
|
[PubMed: 16251902]
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|
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[PubMed: 12203783]
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[Full Text: https://doi.org/10.1002/gcc.10112]
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Schernthaner-Reiter, M. H., Trivellin, G., Stratakis, C. A.
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<strong>Interaction of AIP with protein kinase A (cAMP-dependent protein kinase).</strong>
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Veugelers, M., Wilkes, D., Burton, K., McDermott, D. A., Song, Y., Goldstein, M. M., La Perle, K., Vaughan, C. J., O'Hagan, A., Bennett, K. R., Meyer, B. J., Legius, E., and 27 others.
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<strong>Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.</strong>
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Proc. Nat. Acad. Sci. 101: 14222-14227, 2004.
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[PubMed: 15371594]
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[Full Text: https://doi.org/10.1073/pnas.0405535101]
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Zhang, J., Hupfeld, C. J., Taylor, S. S., Olefsky, J. M., Tsien, R. Y.
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<strong>Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes.</strong>
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Nature 437: 569-573, 2005.
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[PubMed: 16177793]
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[Full Text: https://doi.org/10.1038/nature04140]
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Bao Lige - updated : 02/25/2020<br>Cassandra L. Kniffin - updated : 5/1/2012<br>George E. Tiller - updated : 11/17/2011<br>Cassandra L. Kniffin - updated : 7/11/2011<br>Carol A. Bocchini - updated : 6/3/2009<br>Cassandra L. Kniffin - updated : 8/25/2008<br>Cassandra L. Kniffin - updated : 4/21/2008<br>John A. Phillips, III - updated : 7/18/2007<br>John A. Phillips, III - updated : 7/16/2007<br>Ada Hamosh - updated : 1/30/2006<br>Ada Hamosh - updated : 11/3/2005<br>George E. Tiller - updated : 4/22/2005<br>Ada Hamosh - updated : 3/3/2005<br>Ada Hamosh - updated : 2/25/2005<br>Cassandra L. Kniffin - updated : 1/24/2005<br>Victor A. McKusick - updated : 12/2/2004<br>Victor A. McKusick - updated : 11/26/2003<br>Victor A. McKusick - updated : 1/8/2003<br>John A. Phillips, III - updated : 12/16/2002<br>Victor A. McKusick - updated : 11/11/2002<br>Paul J. Converse - updated : 5/4/2001<br>George E. Tiller - updated : 3/5/2001<br>Anne M. Stumpf - updated : 2/14/2001<br>Victor A. McKusick - updated : 8/29/2000<br>Victor A. McKusick - updated : 8/28/2000
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Victor A. McKusick : 10/16/1986
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