3154 lines
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Entry
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- *601639 - PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, ALPHA; PRKACA
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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">*601639</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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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="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/601639">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<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=ENSG00000072062;t=ENST00000308677" 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=5566" 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=601639" 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 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=ENSG00000072062;t=ENST00000308677" 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_001304349,NM_002730,NM_207518" 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_002730" 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=601639" 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=03382&isoform_id=03382_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/PRKACA" 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/35479,125205,189967,4506055,8489238,8568081,11493951,24980836,46909584,80473661,109138681,119604803,119604804,119604805,119604806,158258000,158261317,221043534,684892539,684892541,748585205" 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/P17612" 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=5566" 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=ENSG00000072062;t=ENST00000308677" 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=PRKACA" 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=PRKACA" 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+5566" 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/PRKACA" 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:5566" 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/5566" 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=chr19&hgg_gene=ENST00000308677.9&hgg_start=14091688&hgg_end=14117762&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601639[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601639[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000072062" 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=PRKACA" 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=PRKACA" 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=PRKACA" 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=PRKACA&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/PA33748" 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:9380" 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/FBgn0000273.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:97592" 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/PRKACA#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:97592" 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/5566/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=5566" 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=WBGene00002189;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-040801-208" 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:5566" 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=PRKACA&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601639
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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, CATALYTIC, ALPHA; PRKACA
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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">
|
|
PROTEIN KINASE A, C-ALPHA SUBUNIT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
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PRKACA/DNAJB1 FUSION GENE, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PRKACA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PRKACA</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/19/373?start=-3&limit=10&highlight=373">19p13.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:14091688-14117762&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'})">19:14,091,688-14,117,762</a> </span>
|
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</em>
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</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>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619142,615830" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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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="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/19/373?start=-3&limit=10&highlight=373">
|
|
19p13.12
|
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</a>
|
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</span>
|
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</td>
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|
|
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<td>
|
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<span class="mim-font">
|
|
Cardioacrofacial dysplasia 1
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/619142"> 619142 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Cushing syndrome, ACTH-independent adrenal, somatic
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/615830"> 615830 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
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<p>Most of the effects of cAMP in the eukaryotic cell are mediated through the phosphorylation of target proteins on serine or threonine residues by the cAMP-dependent protein kinase (<a href="https://enzyme.expasy.org/EC/2.7.1.37" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.7.1.37</a>). The inactive cAMP-dependent protein kinase is a tetramer composed of 2 regulatory and 2 catalytic subunits. The cooperative binding of 4 molecules of cAMP dissociates the enzyme in a regulatory subunit dimer and 2 free active catalytic subunits. In the human, 4 different regulatory (R) subunits (PRKAR1A, <a href="/entry/188830">188830</a>; PRKAR1B, <a href="/entry/176911">176911</a>; PRKAR2A, <a href="/entry/176910">176910</a>; and PRKAR2B, <a href="/entry/176912">176912</a>) and 3 catalytic subunits (PRKACA; PRKACB, <a href="/entry/176892">176892</a>; and PRKACG <a href="/entry/176893">176893</a>) have been identified (summary by <a href="#11" class="mim-tip-reference" title="Tasken, K., Solberg, R., Zhao, Y., Hansson, V., Jahnsen, T., Siciliano, M. J. <strong>The gene encoding the catalytic subunit C-alpha of cAMP-dependent protein kinase (locus PRKACA) localizes to human chromosome region 19p13.1.</strong> Genomics 36: 535-538, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8884279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8884279</a>] [<a href="https://doi.org/10.1006/geno.1996.0501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8884279">Tasken et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8884279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#5" 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; PRKAR1A, <a href="/entry/188830">188830</a>) 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="#5" 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><p><a href="#13" class="mim-tip-reference" title="Zhang, P., Smith-Nguyen, E. V., Keshwani, M. M., Deal, M. S., Kornev, A. P., Taylor, S. S. <strong>Structure and allostery of the PKA RII-beta tetrameric holoenzyme.</strong> Science 335: 712-716, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323819[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323819">Zhang et al. (2012)</a> described the 2.3-angstrom structure of full-length tetrameric RII-beta (PRKAR2B; <a href="/entry/176912">176912</a>)(2):catalytic subunit-alpha(2) holoenzyme. The structure showing a dimer of dimers provided a mechanistic understanding of allosteric activation by cAMP. The heterodimers are anchored together by an interface created by the beta-4/beta-5 loop in the RII-beta subunit, which docks onto the carboxyl-terminal tail of the adjacent C subunit, thereby forcing the C subunit into a fully closed conformation in the absence of nucleotide. Diffusion of magnesium ATP into these crystals trapped not ATP but the reaction products adenosine diphosphate and the phosphorylated RII-beta subunit. This complex has implications for the dissociation-reassociation cycling of PKA. The quaternary structure of the RII-beta tetramer differs appreciably from the model of the RI-alpha tetramer, confirming the small-angle x-ray scattering prediction that the structures of each PKA tetramer are different. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323819" 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>Using PCR and Southern blot analysis, <a href="#11" class="mim-tip-reference" title="Tasken, K., Solberg, R., Zhao, Y., Hansson, V., Jahnsen, T., Siciliano, M. J. <strong>The gene encoding the catalytic subunit C-alpha of cAMP-dependent protein kinase (locus PRKACA) localizes to human chromosome region 19p13.1.</strong> Genomics 36: 535-538, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8884279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8884279</a>] [<a href="https://doi.org/10.1006/geno.1996.0501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8884279">Tasken et al. (1996)</a> assigned the PRKACA gene to chromosome 19. By 2-color fluorescence in situ hybridization, they regionalized the assignment to 19p13.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8884279" 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>Studying hippocampal slices from rats of different ages, <a href="#12" class="mim-tip-reference" title="Yasuda, H., Barth, A. L., Stellwagen, D., Malenka, R. C. <strong>A developmental switch in the signaling cascades for LTP induction.</strong> Nature Neurosci. 6: 15-16, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469130</a>] [<a href="https://doi.org/10.1038/nn985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12469130">Yasuda et al. (2003)</a> found that protein kinase A is required for long-term potentiation (LTP) in neonatal tissue (less than 9 postnatal days). After that time, LTP requires calcium/calmodulin-dependent protein kinase II (see CAMK2A, <a href="/entry/114078">114078</a>). <a href="#12" class="mim-tip-reference" title="Yasuda, H., Barth, A. L., Stellwagen, D., Malenka, R. C. <strong>A developmental switch in the signaling cascades for LTP induction.</strong> Nature Neurosci. 6: 15-16, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469130</a>] [<a href="https://doi.org/10.1038/nn985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12469130">Yasuda et al. (2003)</a> suggested that developmental changes in synapse morphology, including a shift from dendritic shafts to dendritic spines and compartmentalization of calcium, may underlie the changes in kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469130" 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="Lignitto, L., Carlucci, A., Sepe, M., Stefan, E., Cuomo, O., Nistico, R., Scorziello, A., Savoia, C., Garbi, C., Annunziato, L., Feliciello, A. <strong>Control of PKA stability and signalling by the RING ligase praja2.</strong> Nature Cell Biol. 13: 412-422, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21423175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21423175</a>] [<a href="https://doi.org/10.1038/ncb2209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21423175">Lignitto et al. (2011)</a> identified PRAJA2 (PJA2; <a href="/entry/619341">619341</a>) as an A-kinase anchor protein (AKAP) that bound to PKA R subunits and colocalized with PKA in human cells and rat brain. PRAJA2 controlled the stability of R subunits of PKA through ubiquitylation and subsequent proteolysis. This PRAJA2 activity was regulated by PKA catalytic subunits (PKAc), as PKAc regulated abundance of compartmentalized pools of R subunits through phosphorylation of PRAJA2 and recruitment to R subunits, leading to subsequent R proteolysis. Downregulation of R subunits by PRAJA2 prolonged the time of PKAc activation, thereby controlling translocation of PKAc to nucleus, phosphorylation of CREB (CREB1; <a href="/entry/123810">123810</a>) at ser133, and activation of nuclear gene transcription. Downregulation of Praja2 affected nuclear PKAc signaling and LTP in rat brain, indicating that PRAJA2 activity was essential for PKA-mediated long-term memory processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21423175" 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="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://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 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>Fibrolamellar hepatocellular carcinoma (see HCC, <a href="/entry/114550">114550</a>) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. <a href="#4" class="mim-tip-reference" title="Honeyman, J. N., Simon, E. P., Robine, N., Chiaroni-Clarke, R., Darcy, D. G., Lim, I. I. P., Gleason, C. E., Murphy, J. M., Rosenberg, B. R., Teegan, L., Takacs, C. N., Botero, S., Belote, R., Germer, S., Emde, A.-K., Vacic, V., Bhanot, U., LaQuaglia, M. P., Simon, S. M. <strong>Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.</strong> Science 343: 1010-1014, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24578576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24578576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24578576[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1249484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24578576">Honeyman et al. (2014)</a> identified a chimeric transcript that is expressed in fibrolamellar HCC but not in adjacent normal liver and that arises as the result of an approximately 400-kb deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1 (<a href="/entry/604572">604572</a>), a homolog of the molecular chaperone DNAJ, fused in-frame with PRKACA, the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the fibrolamellar HCCs examined (15 of 15) suggests that this genetic alteration contributes to tumor pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24578576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 of 35 patients with overt ACTH-independent Cushing syndrome due to bilateral adrenal adenomas, <a href="#1" class="mim-tip-reference" title="Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others. <strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.</strong> New Eng. J. Med. 370: 1019-1028, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24571724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24571724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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/10.1056/NEJMoa1310359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24571724">Beuschlein et al. (2014)</a> identified germline heterozygous duplications of chromosome 19p13. The duplication ranged in size from 294 kb to 2.7 Mb, but all included the entire PRKACA gene. The 5 patients included an adult mother and son and 3 unrelated boys between 3 and 9 years of age. Four of the patients had a diagnosis of primary pigmented nodular adrenocortical disease (PPNAD4; <a href="/entry/615830">615830</a>). Patient cells showed increased protein levels of the PKA catalytic subunit as well as increased basal protein kinase A activity, consistent with a gain of function. No PRKACA whole-gene duplications were found in the Database of Genomic Variants or in an in-house database of 2,000 persons with intellectual disability, congenital malformations, or both. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" 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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In 8 of 10 cortisol-secreting adrenal adenomas from patients with overt Cushing syndrome (see <a href="/entry/615830">615830</a>), <a href="#1" class="mim-tip-reference" title="Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others. <strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.</strong> New Eng. J. Med. 370: 1019-1028, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24571724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24571724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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/10.1056/NEJMoa1310359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24571724">Beuschlein et al. (2014)</a> identified a somatic heterozygous mutation in the PRKACA gene. Seven of the tumors carried the same L206R mutation (<a href="#0001">601639.0001</a>) that was demonstrated in vitro to result in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. The mutations were found by whole-exome sequencing. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. Overall, 22 (37%) of 59 patients with overt Cushing syndrome due to a unilateral adrenal adenoma carried a somatic heterozygous PRKACA mutation. The molecular and cytogenetic findings provided evidence that PRKACA activation leads to marked excess of cortisol due to constitutive activation of the enzymes that mediate corticotropin-dependent effects on adrenal steroidogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" 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>Simultaneously and independently, <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. <strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong> Science 344: 913-917, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>] [<a href="https://doi.org/10.1126/science.1249480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700472">Cao et al. (2014)</a>, <a href="#8" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. <strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong> Science 344: 917-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24855271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24855271</a>] [<a href="https://doi.org/10.1126/science.1252328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24855271">Sato et al. (2014)</a>, and <a href="#3" class="mim-tip-reference" title="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. <strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong> Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24747643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24747643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24747643">Goh et al. (2014)</a> found the recurrent L206R somatic mutation in adrenocortical tumors derived from patients with clinical Cushing syndrome. The mutations were found by whole-exome sequencing and confirmed in additional cohorts of tumor samples. <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. <strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong> Science 344: 913-917, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>] [<a href="https://doi.org/10.1126/science.1249480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700472">Cao et al. (2014)</a> identified the mutation in up to 69.2% of samples, <a href="#8" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. <strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong> Science 344: 917-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24855271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24855271</a>] [<a href="https://doi.org/10.1126/science.1252328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24855271">Sato et al. (2014)</a> in 52.3% of samples, and <a href="#3" class="mim-tip-reference" title="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. <strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong> Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24747643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24747643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24747643">Goh et al. (2014)</a> in 35% of samples. Each group demonstrated in vitro that the mutation resulted in cAMP-independent activation of protein kinase A with increased substrate phosphorylation. <a href="#8" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. <strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong> Science 344: 917-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24855271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24855271</a>] [<a href="https://doi.org/10.1126/science.1252328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24855271">Sato et al. (2014)</a> and <a href="#3" class="mim-tip-reference" title="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. <strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong> Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24747643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24747643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24747643">Goh et al. (2014)</a> found that the L206R variant disrupted the interface of the catalytic and regulatory subunits, resulting in constitutive activation of protein kinase A and a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24855271+24700472+24747643" 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>Cardioacrofacial Dysplasia 1</em></strong></p><p>
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In affected individuals from 3 unrelated families with cardioacrofacial dysplasia (CAFD1; <a href="/entry/619142">619142</a>), <a href="#7" class="mim-tip-reference" title="Palencia-Campos, A., Aoto, P. C., Machal, E. M. F., Rivera-Barahona, A., Soto-Bielicka, P., Bertinetti, D., Baker, B., Vu, L., Piceci-Sparascio, F., Torrente, I., Boudin, E., Peeters, S., and 30 others. <strong>Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome.</strong> Am. J. Hum. Genet. 107: 977-988, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33058759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33058759</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.09.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33058759">Palencia-Campos et al. (2020)</a> identified heterozygosity or mosaicism for a missense mutation in the PRKACA gene (G137R; <a href="#0002">601639.0002</a>). Functional analysis demonstrated that the mutant PKA holoenzymes were more sensitive to activation by cAMP than wildtype proteins. In addition, the variants inhibited hedgehog (see <a href="/entry/600725">600725</a>) signaling, which the authors suggested as an underlying mechanism for the observed developmental defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33058759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The intracellular second messenger cAMP affects cell physiology by directly interacting with effector molecules that include cyclic nucleotide-gated ion channels, cAMP-regulated G protein exchange factors, and cAMP-dependent protein kinases (PKA). Two catalytic subunits, C-alpha (PRKACA) and C-beta (PRKACB), are expressed in the mouse and mediate the effects of PKA. <a href="#10" class="mim-tip-reference" title="Skalhegg, B. S., Huang, Y., Su, T., Idzerda, R. L., McKnight, G. S., Burton, K. A. <strong>Mutation of the C-alpha subunit of PKA leads to growth retardation and sperm dysfunction.</strong> Molec. Endocr. 16: 630-639, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875122</a>] [<a href="https://doi.org/10.1210/mend.16.3.0793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11875122">Skalhegg et al. (2002)</a> generated a null mutation in the major catalytic subunit of PKA, C-alpha, and observed early postnatal lethality in the majority of C-alpha knockout mice. Surprisingly, a small percentage of C-alpha knockout mice, although runted, survived to adulthood. This growth retardation was not due to decreased GH (<a href="/entry/139250">139250</a>) production but did correlate with a reduction in IGF1 (<a href="/entry/147440">147440</a>) mRNA in the liver and diminished production of the major urinary proteins in kidney. In these animals, compensatory increases in C-beta levels occurred in brain whereas many tissues, including skeletal muscle, heart, and sperm, contained less than 10% of the normal PKA activity. Analysis of sperm in C-alpha knockout males revealed that spermatogenesis progressed normally but that mature sperm had defective forward motility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875122" 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 adrenal adenoma tissue from 7 unrelated women with ACTH-independent adrenal Cushing syndrome (see <a href="/entry/615830">615830</a>), <a href="#1" class="mim-tip-reference" title="Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others. <strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.</strong> New Eng. J. Med. 370: 1019-1028, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24571724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24571724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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/10.1056/NEJMoa1310359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24571724">Beuschlein et al. (2014)</a> identified a somatic heterozygous c.617A-C transversion in the PRKACA gene, resulting in a leu206-to-arg (L206R) substitution at a highly conserved residue in the active-site cleft to which the inhibitory sequence of the regulatory subunit binds. The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project database or in 1,600 in-house exomes. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. In vitro functional expression studies demonstrated that the mutation resulted in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" 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 whole-exome sequencing, <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. <strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong> Science 344: 913-917, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>] [<a href="https://doi.org/10.1126/science.1249480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700472">Cao et al. (2014)</a> identified a somatic mutation in the PRKACA gene in 27 (69.2%) of 39 adrenocortical adenomas. Further screening identified this somatic mutation in 57 (65.5%) of 87 adrenocortical adenomas. Most of the tumors were found in females. <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. <strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong> Science 344: 913-917, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>] [<a href="https://doi.org/10.1126/science.1249480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700472">Cao et al. (2014)</a> referred to this variant as a c.617T-G transversion, resulting in a leu205-to-arg (L205R) substitution. The variant was not present in 13 samples of adrenocorticotropin-independent macronodular adrenocortical hyperplasia (AIMAH), in 6 adrenocortical carcinomas, or in 3 adrenocortical oncocytomas, suggesting that it is specific to adrenocortical adenomas. Structural analysis indicated that the affected residue is a component of the conserved P+1 loop that controls the specific binding between the kinase and its substrates, including the regulatory subunit. Western blot analysis showed increased phosphorylation of PKA substrates, and gene expression analysis showed upregulation of genes involved in steroidogenesis. In vitro studies in 293T cells showed that the L205R mutation had a gain-of-function effect, with increased phosphorylation. However, coimmunoprecipitation studies by <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. <strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong> Science 344: 913-917, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>] [<a href="https://doi.org/10.1126/science.1249480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700472">Cao et al. (2014)</a> showed that mutant PRKACA was pulled down by the PKA regulatory subunit, indicating that this interaction was not interrupted by the L205R mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24700472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. <strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong> Science 344: 917-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24855271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24855271</a>] [<a href="https://doi.org/10.1126/science.1252328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24855271">Sato et al. (2014)</a> identified a somatic c.617T-G transversion in the PRKACA gene, resulting in a leu206-to-arg (L206R) substitution in 4 of 8 adrenocortical tumors derived from patients with corticotropin-independent Cushing syndrome. The mutation was found by whole-exome sequencing. The same L206R mutation was subsequently found in 30 of 57 follow-up cases, 24 of which were confirmed to be somatic. Overall, 52.3% of cases carried this mutation. The L206 residue is located at the interface between the C subunit and the inhibitory R subunit, and the substitution is predicted to cause steric hindrance and to abolish the binding of the C and R subunits, resulting in constitutive cAMP-independent activation of protein kinase A. In vitro studies using purified proteins and HEK293 cells showed that the L206R mutant protein could not bind to wildtype PRKAR1A (<a href="/entry/188830">188830</a>). The mutant protein showed higher basal protein kinase activity compared to wildtype, and this activity was cAMP-independent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24855271" 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="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. <strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong> Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24747643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24747643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24747643">Goh et al. (2014)</a> identified a somatic heterozygous L206R mutation in 13 (35%) of 63 adrenocortical adenomas derived from patients with clinical Cushing syndrome. The initial mutations were found by exome sequencing. The L206R mutation occurs at a highly conserved residue where the regulatory subunit binds to the catalytic PRKACA subunit. Immunoprecipitation studies showed that the mutant protein did not bind to the PRKAR1A subunit, and protein blot analysis detected increased phosphorylation of PRKACA substrates associated with the mutant protein compared to wildtype. The findings were consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24747643" 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>.0002 CARDIOACROFACIAL DYSPLASIA 1</strong>
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PRKACA, GLY137ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs148280386 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs148280386;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=rs148280386" 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=rs148280386" 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=RCV001271119 OR RCV002509646" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001271119, RCV002509646" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001271119...</a>
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<p>In affected individuals from 3 unrelated families from Egypt (family 1), Belgium (family 2), and Italy (family 3) with cardioacrofacial dysplasia (CAFD1; <a href="/entry/619142">619142</a>), <a href="#7" class="mim-tip-reference" title="Palencia-Campos, A., Aoto, P. C., Machal, E. M. F., Rivera-Barahona, A., Soto-Bielicka, P., Bertinetti, D., Baker, B., Vu, L., Piceci-Sparascio, F., Torrente, I., Boudin, E., Peeters, S., and 30 others. <strong>Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome.</strong> Am. J. Hum. Genet. 107: 977-988, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33058759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33058759</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.09.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33058759">Palencia-Campos et al. (2020)</a> identified heterozygosity or mosaicism for a c.409G-A transition (c.409G-A, NM_002730.4) in the PRKACA gene, resulting in a gly137-to-arg (G137R) substitution at a highly conserved residue at a tethering surface that interacts with regulatory proteins. The G137R variant was not found in the gnomAD database. In the Egyptian proband (P1), the variant was mosaic, with a variant allele fraction (VAF) of 0.28; his 2 affected offspring for whom DNA was available carried the variant in heterozygous state. The unaffected father of the Belgian proband (P2) was mosaic for G137R (VAF 0.16), but the variant was germline-transmitted in P2 (VAF 0.55) and her affected fetus (VAF 0.46). The mutation was found to have occurred de novo in the Italian proband (P3). Fluorescence polarization assays of purified holoenzymes showed greater sensitivity of the mutant holoenzyme to lower cAMP concentrations than with wildtype protein, and PepTag assay in transfected HEK293 cells showed increased kinase activity with the G137R mutant at low cAMP concentrations compared to wildtype protein. Analysis of hedgehog (see <a href="/entry/600725">600725</a>) pathway signaling in retrotransduced NIH 3T3 cells after stimulation with the SMO (<a href="/entry/601500">601500</a>) agonist SAG revealed that the G137R mutant impairs SAG-mediated inactivation of PKA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33058759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Beuschlein2014" class="mim-anchor"></a>
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Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others.
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<strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.</strong>
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New Eng. J. Med. 370: 1019-1028, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24571724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24571724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1310359" target="_blank">Full Text</a>]
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Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others.
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<strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong>
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Science 344: 913-917, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24700472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1249480" target="_blank">Full Text</a>]
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Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P.
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<strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong>
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Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24747643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24747643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24747643" 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/ng.2956" target="_blank">Full Text</a>]
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Honeyman, J. N., Simon, E. P., Robine, N., Chiaroni-Clarke, R., Darcy, D. G., Lim, I. I. P., Gleason, C. E., Murphy, J. M., Rosenberg, B. R., Teegan, L., Takacs, C. N., Botero, S., Belote, R., Germer, S., Emde, A.-K., Vacic, V., Bhanot, U., LaQuaglia, M. P., Simon, S. M.
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<strong>Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.</strong>
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Science 343: 1010-1014, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24578576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24578576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24578576[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24578576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1249484" target="_blank">Full Text</a>]
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Kim, C., Xuong, N.-H., Taylor, S. S.
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<strong>Crystal structure of a complex between the catalytic and regulatory (RI-alpha) subunits of PKA.</strong>
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Science 307: 690-696, 2005.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1104607" target="_blank">Full Text</a>]
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Lignitto, L., Carlucci, A., Sepe, M., Stefan, E., Cuomo, O., Nistico, R., Scorziello, A., Savoia, C., Garbi, C., Annunziato, L., Feliciello, A.
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<strong>Control of PKA stability and signalling by the RING ligase praja2.</strong>
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Nature Cell Biol. 13: 412-422, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21423175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21423175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21423175" 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/ncb2209" target="_blank">Full Text</a>]
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<a id="Palencia-Campos2020" class="mim-anchor"></a>
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Palencia-Campos, A., Aoto, P. C., Machal, E. M. F., Rivera-Barahona, A., Soto-Bielicka, P., Bertinetti, D., Baker, B., Vu, L., Piceci-Sparascio, F., Torrente, I., Boudin, E., Peeters, S., and 30 others.
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<strong>Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome.</strong>
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Am. J. Hum. Genet. 107: 977-988, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33058759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33058759</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33058759" 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.2020.09.005" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Sato2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others.
|
|
<strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong>
|
|
Science 344: 917-920, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24855271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24855271</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24855271" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1252328" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Schernthaner-Reiter2018" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
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.
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|
|
|
|
|
[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy166" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Skalhegg2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Skalhegg, B. S., Huang, Y., Su, T., Idzerda, R. L., McKnight, G. S., Burton, K. A.
|
|
<strong>Mutation of the C-alpha subunit of PKA leads to growth retardation and sperm dysfunction.</strong>
|
|
Molec. Endocr. 16: 630-639, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875122</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/mend.16.3.0793" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Tasken1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tasken, K., Solberg, R., Zhao, Y., Hansson, V., Jahnsen, T., Siciliano, M. J.
|
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<strong>The gene encoding the catalytic subunit C-alpha of cAMP-dependent protein kinase (locus PRKACA) localizes to human chromosome region 19p13.1.</strong>
|
|
Genomics 36: 535-538, 1996.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8884279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8884279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8884279" 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/10.1006/geno.1996.0501" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Yasuda2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yasuda, H., Barth, A. L., Stellwagen, D., Malenka, R. C.
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<strong>A developmental switch in the signaling cascades for LTP induction.</strong>
|
|
Nature Neurosci. 6: 15-16, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469130</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469130" 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/nn985" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Zhang2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, P., Smith-Nguyen, E. V., Keshwani, M. M., Deal, M. S., Kornev, A. P., Taylor, S. S.
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<strong>Structure and allostery of the PKA RII-beta tetrameric holoenzyme.</strong>
|
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Science 335: 712-716, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323819[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1213979" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 05/21/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 12/28/2020<br>Bao Lige - updated : 02/25/2020<br>Cassandra L. Kniffin - updated : 7/7/2014<br>Cassandra L. Kniffin - updated : 6/3/2014<br>Ada Hamosh - updated : 3/31/2014<br>Ada Hamosh - updated : 2/27/2012<br>Ada Hamosh - updated : 2/25/2005<br>Cassandra L. Kniffin - updated : 12/3/2002<br>John A. Phillips, III - updated : 10/10/2002
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Lori M. Kelman : 1/21/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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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mgross : 05/21/2021
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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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alopez : 12/28/2020<br>alopez : 12/28/2020<br>mgross : 02/25/2020<br>alopez : 02/02/2018<br>carol : 08/19/2014<br>mcolton : 7/7/2014<br>ckniffin : 7/7/2014<br>carol : 6/4/2014<br>carol : 6/4/2014<br>mcolton : 6/3/2014<br>ckniffin : 6/3/2014<br>alopez : 3/31/2014<br>alopez : 2/28/2012<br>alopez : 2/28/2012<br>terry : 2/27/2012<br>wwang : 3/3/2005<br>terry : 2/25/2005<br>alopez : 1/9/2003<br>alopez : 12/3/2002<br>ckniffin : 12/3/2002<br>alopez : 10/10/2002<br>jamie : 1/21/1997<br>jamie : 1/21/1997
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</span>
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</div>
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</div>
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</div>
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</div>
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</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">
|
|
<strong>*</strong> 601639
|
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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, CATALYTIC, ALPHA; PRKACA
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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">
|
|
PROTEIN KINASE A, C-ALPHA SUBUNIT
|
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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">
|
|
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">
|
|
PRKACA/DNAJB1 FUSION GENE, 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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: PRKACA</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: 19p13.12
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 19:14,091,688-14,117,762 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
19p13.12
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardioacrofacial dysplasia 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619142
|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
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</tr>
|
|
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|
|
|
|
|
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cushing syndrome, ACTH-independent adrenal, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615830
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
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|
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|
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|
|
</tbody>
|
|
</table>
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|
</div>
|
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</div>
|
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<div>
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<br />
|
|
</div>
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<span class="mim-text-font">
|
|
<p>Most of the effects of cAMP in the eukaryotic cell are mediated through the phosphorylation of target proteins on serine or threonine residues by the cAMP-dependent protein kinase (EC 2.7.1.37). The inactive cAMP-dependent protein kinase is a tetramer composed of 2 regulatory and 2 catalytic subunits. The cooperative binding of 4 molecules of cAMP dissociates the enzyme in a regulatory subunit dimer and 2 free active catalytic subunits. In the human, 4 different regulatory (R) subunits (PRKAR1A, 188830; PRKAR1B, 176911; PRKAR2A, 176910; and PRKAR2B, 176912) and 3 catalytic subunits (PRKACA; PRKACB, 176892; and PRKACG 176893) have been identified (summary by Tasken et al., 1996). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><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; PRKAR1A, 188830) 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><p>Zhang et al. (2012) described the 2.3-angstrom structure of full-length tetrameric RII-beta (PRKAR2B; 176912)(2):catalytic subunit-alpha(2) holoenzyme. The structure showing a dimer of dimers provided a mechanistic understanding of allosteric activation by cAMP. The heterodimers are anchored together by an interface created by the beta-4/beta-5 loop in the RII-beta subunit, which docks onto the carboxyl-terminal tail of the adjacent C subunit, thereby forcing the C subunit into a fully closed conformation in the absence of nucleotide. Diffusion of magnesium ATP into these crystals trapped not ATP but the reaction products adenosine diphosphate and the phosphorylated RII-beta subunit. This complex has implications for the dissociation-reassociation cycling of PKA. The quaternary structure of the RII-beta tetramer differs appreciably from the model of the RI-alpha tetramer, confirming the small-angle x-ray scattering prediction that the structures of each PKA tetramer are different. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Using PCR and Southern blot analysis, Tasken et al. (1996) assigned the PRKACA gene to chromosome 19. By 2-color fluorescence in situ hybridization, they regionalized the assignment to 19p13.1. </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>Studying hippocampal slices from rats of different ages, Yasuda et al. (2003) found that protein kinase A is required for long-term potentiation (LTP) in neonatal tissue (less than 9 postnatal days). After that time, LTP requires calcium/calmodulin-dependent protein kinase II (see CAMK2A, 114078). Yasuda et al. (2003) suggested that developmental changes in synapse morphology, including a shift from dendritic shafts to dendritic spines and compartmentalization of calcium, may underlie the changes in kinase activity. </p><p>Lignitto et al. (2011) identified PRAJA2 (PJA2; 619341) as an A-kinase anchor protein (AKAP) that bound to PKA R subunits and colocalized with PKA in human cells and rat brain. PRAJA2 controlled the stability of R subunits of PKA through ubiquitylation and subsequent proteolysis. This PRAJA2 activity was regulated by PKA catalytic subunits (PKAc), as PKAc regulated abundance of compartmentalized pools of R subunits through phosphorylation of PRAJA2 and recruitment to R subunits, leading to subsequent R proteolysis. Downregulation of R subunits by PRAJA2 prolonged the time of PKAc activation, thereby controlling translocation of PKAc to nucleus, phosphorylation of CREB (CREB1; 123810) at ser133, and activation of nuclear gene transcription. Downregulation of Praja2 affected nuclear PKAc signaling and LTP in rat brain, indicating that PRAJA2 activity was essential for PKA-mediated long-term memory processes. </p><p>Schernthaner-Reiter et al. (2018) found that endogenous Aip (605555) physically interacted and colocalized with R1-alpha and C-alpha 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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<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>Fibrolamellar hepatocellular carcinoma (see HCC, 114550) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. Honeyman et al. (2014) identified a chimeric transcript that is expressed in fibrolamellar HCC but not in adjacent normal liver and that arises as the result of an approximately 400-kb deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1 (604572), a homolog of the molecular chaperone DNAJ, fused in-frame with PRKACA, the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the fibrolamellar HCCs examined (15 of 15) suggests that this genetic alteration contributes to tumor pathogenesis. </p><p>In 5 of 35 patients with overt ACTH-independent Cushing syndrome due to bilateral adrenal adenomas, Beuschlein et al. (2014) identified germline heterozygous duplications of chromosome 19p13. The duplication ranged in size from 294 kb to 2.7 Mb, but all included the entire PRKACA gene. The 5 patients included an adult mother and son and 3 unrelated boys between 3 and 9 years of age. Four of the patients had a diagnosis of primary pigmented nodular adrenocortical disease (PPNAD4; 615830). Patient cells showed increased protein levels of the PKA catalytic subunit as well as increased basal protein kinase A activity, consistent with a gain of function. No PRKACA whole-gene duplications were found in the Database of Genomic Variants or in an in-house database of 2,000 persons with intellectual disability, congenital malformations, or both. </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>Somatic ACTH-Independent Adrenal Cushing Syndrome</em></strong></p><p>
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In 8 of 10 cortisol-secreting adrenal adenomas from patients with overt Cushing syndrome (see 615830), Beuschlein et al. (2014) identified a somatic heterozygous mutation in the PRKACA gene. Seven of the tumors carried the same L206R mutation (601639.0001) that was demonstrated in vitro to result in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. The mutations were found by whole-exome sequencing. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. Overall, 22 (37%) of 59 patients with overt Cushing syndrome due to a unilateral adrenal adenoma carried a somatic heterozygous PRKACA mutation. The molecular and cytogenetic findings provided evidence that PRKACA activation leads to marked excess of cortisol due to constitutive activation of the enzymes that mediate corticotropin-dependent effects on adrenal steroidogenesis. </p><p>Simultaneously and independently, Cao et al. (2014), Sato et al. (2014), and Goh et al. (2014) found the recurrent L206R somatic mutation in adrenocortical tumors derived from patients with clinical Cushing syndrome. The mutations were found by whole-exome sequencing and confirmed in additional cohorts of tumor samples. Cao et al. (2014) identified the mutation in up to 69.2% of samples, Sato et al. (2014) in 52.3% of samples, and Goh et al. (2014) in 35% of samples. Each group demonstrated in vitro that the mutation resulted in cAMP-independent activation of protein kinase A with increased substrate phosphorylation. Sato et al. (2014) and Goh et al. (2014) found that the L206R variant disrupted the interface of the catalytic and regulatory subunits, resulting in constitutive activation of protein kinase A and a gain-of-function effect. </p><p><strong><em>Cardioacrofacial Dysplasia 1</em></strong></p><p>
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In affected individuals from 3 unrelated families with cardioacrofacial dysplasia (CAFD1; 619142), Palencia-Campos et al. (2020) identified heterozygosity or mosaicism for a missense mutation in the PRKACA gene (G137R; 601639.0002). Functional analysis demonstrated that the mutant PKA holoenzymes were more sensitive to activation by cAMP than wildtype proteins. In addition, the variants inhibited hedgehog (see 600725) signaling, which the authors suggested as an underlying mechanism for the observed developmental defects. </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>The intracellular second messenger cAMP affects cell physiology by directly interacting with effector molecules that include cyclic nucleotide-gated ion channels, cAMP-regulated G protein exchange factors, and cAMP-dependent protein kinases (PKA). Two catalytic subunits, C-alpha (PRKACA) and C-beta (PRKACB), are expressed in the mouse and mediate the effects of PKA. Skalhegg et al. (2002) generated a null mutation in the major catalytic subunit of PKA, C-alpha, and observed early postnatal lethality in the majority of C-alpha knockout mice. Surprisingly, a small percentage of C-alpha knockout mice, although runted, survived to adulthood. This growth retardation was not due to decreased GH (139250) production but did correlate with a reduction in IGF1 (147440) mRNA in the liver and diminished production of the major urinary proteins in kidney. In these animals, compensatory increases in C-beta levels occurred in brain whereas many tissues, including skeletal muscle, heart, and sperm, contained less than 10% of the normal PKA activity. Analysis of sperm in C-alpha knockout males revealed that spermatogenesis progressed normally but that mature sperm had defective forward motility. </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>2 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CUSHING SYNDROME, ACTH-INDEPENDENT ADRENAL, SOMATIC</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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PRKACA, LEU206ARG
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<br />
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SNP: rs386352352,
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ClinVar: RCV000119834, RCV000122662, RCV002508139
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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 adrenal adenoma tissue from 7 unrelated women with ACTH-independent adrenal Cushing syndrome (see 615830), Beuschlein et al. (2014) identified a somatic heterozygous c.617A-C transversion in the PRKACA gene, resulting in a leu206-to-arg (L206R) substitution at a highly conserved residue in the active-site cleft to which the inhibitory sequence of the regulatory subunit binds. The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project database or in 1,600 in-house exomes. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. In vitro functional expression studies demonstrated that the mutation resulted in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. </p><p>Using whole-exome sequencing, Cao et al. (2014) identified a somatic mutation in the PRKACA gene in 27 (69.2%) of 39 adrenocortical adenomas. Further screening identified this somatic mutation in 57 (65.5%) of 87 adrenocortical adenomas. Most of the tumors were found in females. Cao et al. (2014) referred to this variant as a c.617T-G transversion, resulting in a leu205-to-arg (L205R) substitution. The variant was not present in 13 samples of adrenocorticotropin-independent macronodular adrenocortical hyperplasia (AIMAH), in 6 adrenocortical carcinomas, or in 3 adrenocortical oncocytomas, suggesting that it is specific to adrenocortical adenomas. Structural analysis indicated that the affected residue is a component of the conserved P+1 loop that controls the specific binding between the kinase and its substrates, including the regulatory subunit. Western blot analysis showed increased phosphorylation of PKA substrates, and gene expression analysis showed upregulation of genes involved in steroidogenesis. In vitro studies in 293T cells showed that the L205R mutation had a gain-of-function effect, with increased phosphorylation. However, coimmunoprecipitation studies by Cao et al. (2014) showed that mutant PRKACA was pulled down by the PKA regulatory subunit, indicating that this interaction was not interrupted by the L205R mutation. </p><p>Sato et al. (2014) identified a somatic c.617T-G transversion in the PRKACA gene, resulting in a leu206-to-arg (L206R) substitution in 4 of 8 adrenocortical tumors derived from patients with corticotropin-independent Cushing syndrome. The mutation was found by whole-exome sequencing. The same L206R mutation was subsequently found in 30 of 57 follow-up cases, 24 of which were confirmed to be somatic. Overall, 52.3% of cases carried this mutation. The L206 residue is located at the interface between the C subunit and the inhibitory R subunit, and the substitution is predicted to cause steric hindrance and to abolish the binding of the C and R subunits, resulting in constitutive cAMP-independent activation of protein kinase A. In vitro studies using purified proteins and HEK293 cells showed that the L206R mutant protein could not bind to wildtype PRKAR1A (188830). The mutant protein showed higher basal protein kinase activity compared to wildtype, and this activity was cAMP-independent. </p><p>Goh et al. (2014) identified a somatic heterozygous L206R mutation in 13 (35%) of 63 adrenocortical adenomas derived from patients with clinical Cushing syndrome. The initial mutations were found by exome sequencing. The L206R mutation occurs at a highly conserved residue where the regulatory subunit binds to the catalytic PRKACA subunit. Immunoprecipitation studies showed that the mutant protein did not bind to the PRKAR1A subunit, and protein blot analysis detected increased phosphorylation of PRKACA substrates associated with the mutant protein compared to wildtype. The findings were consistent with a gain of function. </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 CARDIOACROFACIAL DYSPLASIA 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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PRKACA, GLY137ARG
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<br />
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SNP: rs148280386,
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ClinVar: RCV001271119, RCV002509646
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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 individuals from 3 unrelated families from Egypt (family 1), Belgium (family 2), and Italy (family 3) with cardioacrofacial dysplasia (CAFD1; 619142), Palencia-Campos et al. (2020) identified heterozygosity or mosaicism for a c.409G-A transition (c.409G-A, NM_002730.4) in the PRKACA gene, resulting in a gly137-to-arg (G137R) substitution at a highly conserved residue at a tethering surface that interacts with regulatory proteins. The G137R variant was not found in the gnomAD database. In the Egyptian proband (P1), the variant was mosaic, with a variant allele fraction (VAF) of 0.28; his 2 affected offspring for whom DNA was available carried the variant in heterozygous state. The unaffected father of the Belgian proband (P2) was mosaic for G137R (VAF 0.16), but the variant was germline-transmitted in P2 (VAF 0.55) and her affected fetus (VAF 0.46). The mutation was found to have occurred de novo in the Italian proband (P3). Fluorescence polarization assays of purified holoenzymes showed greater sensitivity of the mutant holoenzyme to lower cAMP concentrations than with wildtype protein, and PepTag assay in transfected HEK293 cells showed increased kinase activity with the G137R mutant at low cAMP concentrations compared to wildtype protein. Analysis of hedgehog (see 600725) pathway signaling in retrotransduced NIH 3T3 cells after stimulation with the SMO (601500) agonist SAG revealed that the G137R mutant impairs SAG-mediated inactivation of PKA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others.
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<strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.</strong>
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New Eng. J. Med. 370: 1019-1028, 2014.
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[PubMed: 24571724]
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[Full Text: https://doi.org/10.1056/NEJMoa1310359]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others.
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<strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong>
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Science 344: 913-917, 2014.
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[PubMed: 24700472]
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[Full Text: https://doi.org/10.1126/science.1249480]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P.
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<strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong>
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|
Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.
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[PubMed: 24747643]
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[Full Text: https://doi.org/10.1038/ng.2956]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Honeyman, J. N., Simon, E. P., Robine, N., Chiaroni-Clarke, R., Darcy, D. G., Lim, I. I. P., Gleason, C. E., Murphy, J. M., Rosenberg, B. R., Teegan, L., Takacs, C. N., Botero, S., Belote, R., Germer, S., Emde, A.-K., Vacic, V., Bhanot, U., LaQuaglia, M. P., Simon, S. M.
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<strong>Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.</strong>
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Science 343: 1010-1014, 2014.
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[PubMed: 24578576]
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[Full Text: https://doi.org/10.1126/science.1249484]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kim, C., Xuong, N.-H., Taylor, S. S.
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<strong>Crystal structure of a complex between the catalytic and regulatory (RI-alpha) subunits of PKA.</strong>
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Science 307: 690-696, 2005.
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[PubMed: 15692043]
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[Full Text: https://doi.org/10.1126/science.1104607]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lignitto, L., Carlucci, A., Sepe, M., Stefan, E., Cuomo, O., Nistico, R., Scorziello, A., Savoia, C., Garbi, C., Annunziato, L., Feliciello, A.
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<strong>Control of PKA stability and signalling by the RING ligase praja2.</strong>
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Nature Cell Biol. 13: 412-422, 2011.
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[PubMed: 21423175]
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[Full Text: https://doi.org/10.1038/ncb2209]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Palencia-Campos, A., Aoto, P. C., Machal, E. M. F., Rivera-Barahona, A., Soto-Bielicka, P., Bertinetti, D., Baker, B., Vu, L., Piceci-Sparascio, F., Torrente, I., Boudin, E., Peeters, S., and 30 others.
|
|
<strong>Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome.</strong>
|
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Am. J. Hum. Genet. 107: 977-988, 2020.
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[PubMed: 33058759]
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[Full Text: https://doi.org/10.1016/j.ajhg.2020.09.005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others.
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<strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong>
|
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Science 344: 917-920, 2014.
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[PubMed: 24855271]
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[Full Text: https://doi.org/10.1126/science.1252328]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schernthaner-Reiter, M. H., Trivellin, G., Stratakis, C. A.
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Skalhegg, B. S., Huang, Y., Su, T., Idzerda, R. L., McKnight, G. S., Burton, K. A.
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<strong>Mutation of the C-alpha subunit of PKA leads to growth retardation and sperm dysfunction.</strong>
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Tasken, K., Solberg, R., Zhao, Y., Hansson, V., Jahnsen, T., Siciliano, M. J.
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<strong>The gene encoding the catalytic subunit C-alpha of cAMP-dependent protein kinase (locus PRKACA) localizes to human chromosome region 19p13.1.</strong>
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Yasuda, H., Barth, A. L., Stellwagen, D., Malenka, R. C.
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<strong>A developmental switch in the signaling cascades for LTP induction.</strong>
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Zhang, P., Smith-Nguyen, E. V., Keshwani, M. M., Deal, M. S., Kornev, A. P., Taylor, S. S.
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<strong>Structure and allostery of the PKA RII-beta tetrameric holoenzyme.</strong>
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Science 335: 712-716, 2012.
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[PubMed: 22323819]
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[Full Text: https://doi.org/10.1126/science.1213979]
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