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<title>
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Entry
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- *176894 - PROTEIN KINASE, cGMP-DEPENDENT, REGULATORY, TYPE I; PRKG1
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- OMIM
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<li class="dropdown-header">
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</form>
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<div class="row">
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<p />
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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</div>
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*176894</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/176894">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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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=ENSG00000185532;t=ENST00000373980" 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=5592" 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=176894" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000185532;t=ENST00000373980" 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_001098512,NM_001374781,NM_001374782,NM_006258,XM_011539952,XM_017016413" 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_006258" 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=176894" 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=08910&isoform_id=08910_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/PRKG1" 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/31709,1255602,3063840,3063842,6225588,10835242,38571600,117558780,119574525,119574526,148342515,148612818,193787509,194390286,767963270,1034568775,1764714881,1764714897,2462520068,2462520070,2462520072" 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/Q13976" 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=5592" 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=ENSG00000185532;t=ENST00000373980" 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=PRKG1" 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=PRKG1" 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+5592" 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/PRKG1" 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:5592" 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/5592" 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=chr10&hgg_gene=ENST00000373980.11&hgg_start=50990888&hgg_end=52298350&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9414" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176894[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176894[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/ENSG00000185532" 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=PRKG1" 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=PRKG1" 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=PRKG1" 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=PRKG1&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/PA33777" 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:9414" 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/FBgn0000721.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:108174" 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/PRKG1#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:108174" 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/5592/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=5592" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001173;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001173 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00015650;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00015650 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1308" 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:5592" 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=PRKG1&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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176894
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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, cGMP-DEPENDENT, REGULATORY, TYPE I; PRKG1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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cGMP-DEPENDENT PROTEIN KINASE, TYPE I, BETA; cGKI-BETA<br />
|
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PRKGR1B
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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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cGMP-DEPENDENT PROTEIN KINASE, TYPE I, ALPHA, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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cGKI-ALPHA, 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=PRKG1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PRKG1</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/10/200?start=-3&limit=10&highlight=200">10q11.23-q21.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:50990888-52298350&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'})">10:50,990,888-52,298,350</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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10q11.23-q21.1
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Aortic aneurysm, familial thoracic 8
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<a href="/entry/615436"> 615436 </a>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/176894" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/176894" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>Cyclic GMP and cyclic GMP-dependent protein kinase play important roles in physiologic processes such as relaxation of vascular smooth muscle and inhibition of platelet aggregation. Two main forms of cGK have been identified: a soluble form designated type I and an intrinsic membrane-bound form designated type II. <a href="#11" class="mim-tip-reference" title="Sandberg, M., Natarajan, V., Ronander, I., Kalderon, D., Walter, U., Lohmann, S. M., Jahnsen, T. <strong>Molecular cloning and predicted full-length amino acid sequence of the type I beta isozyme of cGMP-dependent protein kinase from human placenta: tissue distribution and developmental changes in rat.</strong> FEBS Lett. 255: 321-329, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2792381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2792381</a>] [<a href="https://doi.org/10.1016/0014-5793(89)81114-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2792381">Sandberg et al. (1989)</a> isolated and characterized cDNA clones for the type I beta isozyme from human placenta libraries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2792381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Tamura, N., Itoh, H., Ogawa, Y., Nakagawa, O., Harada, M., Chun, T.-H., Suga, S., Yoshimasa, T., Nakao, K. <strong>cDNA cloning and gene expression of human type I-alpha cGMP-dependent protein kinase.</strong> Hypertension 27: 552-557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8613202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8613202</a>] [<a href="https://doi.org/10.1161/01.hyp.27.3.552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8613202">Tamura et al. (1996)</a> cloned a human cGKI-alpha cDNA by RT-PCR of aorta RNA using primers based on the sequence of a bovine cGKI-alpha cDNA. The predicted 671-amino acid human cGKI-alpha protein is nearly identical to bovine cGKI-alpha. Based on Southern blot and sequence analyses, <a href="#12" class="mim-tip-reference" title="Tamura, N., Itoh, H., Ogawa, Y., Nakagawa, O., Harada, M., Chun, T.-H., Suga, S., Yoshimasa, T., Nakao, K. <strong>cDNA cloning and gene expression of human type I-alpha cGMP-dependent protein kinase.</strong> Hypertension 27: 552-557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8613202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8613202</a>] [<a href="https://doi.org/10.1161/01.hyp.27.3.552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8613202">Tamura et al. (1996)</a> suggested that cGKI-alpha and cGKI-beta are generated by alternative splicing of a single gene. By Northern blot analysis, cGKI-alpha was abundantly expressed as a 7.0-kb mRNA in aorta, heart, kidneys and adrenals; the 7.0-kb cGKI-beta mRNA was abundantly expressed only in the uterus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8613202" 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="Orstavik, S., Natarajan, V., Tasken, K., Jahnsen, T., Sandberg, M. <strong>Characterization of the human gene encoding the type I-alpha and type I-beta cGMP-dependent protein kinase (PRKG1).</strong> Genomics 42: 311-318, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192852</a>] [<a href="https://doi.org/10.1006/geno.1997.4743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192852">Orstavik et al. (1997)</a> noted that type I cGK is a homodimer, with each monomer containing a regulatory cGMP-binding domain and a catalytic domain. By Northern blot analysis, they showed that type I cGK-alpha mRNA was most abundant in lung and placenta, while type I cGK-beta was expressed at highest levels in bladder, uterus, adrenal gland, and fallopian tube. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192852" 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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</span>
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<br />
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<div>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#6" class="mim-tip-reference" title="Orstavik, S., Natarajan, V., Tasken, K., Jahnsen, T., Sandberg, M. <strong>Characterization of the human gene encoding the type I-alpha and type I-beta cGMP-dependent protein kinase (PRKG1).</strong> Genomics 42: 311-318, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192852</a>] [<a href="https://doi.org/10.1006/geno.1997.4743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192852">Orstavik et al. (1997)</a> reported that the type I cGK gene contains 19 exons spanning at least 220 kb. The first 2 exons, which the authors called 1-alpha and 1-beta, are used alternatively and encode the alpha isoform- and beta isoform-specific sequences. <a href="#6" class="mim-tip-reference" title="Orstavik, S., Natarajan, V., Tasken, K., Jahnsen, T., Sandberg, M. <strong>Characterization of the human gene encoding the type I-alpha and type I-beta cGMP-dependent protein kinase (PRKG1).</strong> Genomics 42: 311-318, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192852</a>] [<a href="https://doi.org/10.1006/geno.1997.4743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192852">Orstavik et al. (1997)</a> noted that 5 of the 7 splice sites in the Drosophila melanogaster DG2 gene, which encodes a cGK, are also present in the human type I cGK gene. They reported that levels of the DG2-encoded cGK in Drosophila affect food-search behavior and account for a naturally occurring behavioral polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192852" 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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<br />
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>By Southern blots of human/hamster somatic cell hybrids, <a href="#7" class="mim-tip-reference" title="Orstavik, S., Sandberg, M., Berube, D., Natarajan, V., Simard, J., Walter, U., Gagne, R., Hansson, V., Jahnsen, T. <strong>Localization of the human gene for type I cyclic GMP-dependent protein kinase to chromosome 10.</strong> Cytogenet. Cell Genet. 59: 270-273, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1544322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1544322</a>] [<a href="https://doi.org/10.1159/000133267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1544322">Orstavik et al. (1992)</a> localized the PRKGR1B gene to chromosome 10. The gene was regionally localized to 10q11.2 by in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1544322" 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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<br />
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<a id="geneFunction" class="mim-anchor"></a>
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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Gene Function</strong>
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<p>By yeast 2-hybrid analysis and immunoprecipitation of mouse testis, <a href="#14" class="mim-tip-reference" title="Yuasa, K., Omori, K., Yanaka, N. <strong>Binding and phosphorylation of a novel male germ cell-specific cGMP-dependent protein kinase-anchoring protein by cGMP-dependent protein kinase I-alpha.</strong> J. Biol. Chem. 275: 4897-4905, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10671526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10671526</a>] [<a href="https://doi.org/10.1074/jbc.275.7.4897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10671526">Yuasa et al. (2000)</a> showed that mouse Gkap42 (GKAP1; <a href="/entry/611356">611356</a>) interacted with cGKI-alpha. Gcap42 was phosphorylated by cGKI-alpha in intact cells. A kinase-deficient mutant of cGKI-alpha stably associated with Gkap42, and binding of cGMP to cGKI-alpha facilitated their release from Gkap42. <a href="#14" class="mim-tip-reference" title="Yuasa, K., Omori, K., Yanaka, N. <strong>Binding and phosphorylation of a novel male germ cell-specific cGMP-dependent protein kinase-anchoring protein by cGMP-dependent protein kinase I-alpha.</strong> J. Biol. Chem. 275: 4897-4905, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10671526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10671526</a>] [<a href="https://doi.org/10.1074/jbc.275.7.4897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10671526">Yuasa et al. (2000)</a> concluded that Gkap42 may function as an anchoring protein for cGKI-alpha and that cGKI-alpha may participate in germ cell development through phosphorylation of Golgi-associated proteins, such as GKAP42. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10671526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Li, Z., Xi, X., Gu, M., Feil, R., Ye, R. D., Eigenthaler, M., Hofmann, F., Du, X. <strong>A stimulatory role for cGMP-dependent protein kinase in platelet activation.</strong> Cell 112: 77-86, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526795</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01254-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12526795">Li et al. (2003)</a> showed that PRKG1 plays an important stimulatory role in platelet activation. Expression of recombinant PRKG1 in a reconstituted cell model enhanced von Willebrand factor (VWF; <a href="/entry/613160">613160</a>)-induced activation of the platelet integrin alpha-IIb (<a href="/entry/607759">607759</a>)/beta-3 (<a href="/entry/173470">173470</a>). Prkg1 knockout mice showed impaired platelet responses to VWF or low doses of thrombin and prolonged bleeding time. Human platelet aggregation induced by VWF or low-dose thrombin was inhibited by PRKG1 inhibitors but enhanced by cGMP. Furthermore, a cGMP-enhancing agent, sildenafil, promoted VWF- or thrombin-induced platelet aggregation. The cGMP-stimulated platelet responses were biphasic, consisting of an initial transient stimulatory response that promoted platelet aggregation and a subsequent inhibitory response that limited the size of thrombi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12526795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Burgoyne, J. R., Madhani, M., Cuello, F., Charles, R. L., Brennan, J. P., Schroder, E., Browning, D. D., Eaton, P. <strong>Cysteine redox sensor in PKGI-alpha enables oxidant-induced activation.</strong> Science 317: 1393-1397, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17717153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17717153</a>] [<a href="https://doi.org/10.1126/science.1144318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17717153">Burgoyne et al. (2007)</a> found that the cGMP-dependent protein kinase PKG functions directly as a redox sensor. The I-alpha isoform, PKGI-alpha, formed an interprotein disulfide linking its 2 subunits in cells exposed to exogenous hydrogen peroxide. This oxidation directly activated the kinase in vitro, and in rat cells and tissues. The affinity of the kinase for substrates it phosphorylates was enhanced by disulfide formation. This oxidation-induced activation represents an alternate mechanism for regulation along with the classic activation involving nitric oxide and cGMP. <a href="#1" class="mim-tip-reference" title="Burgoyne, J. R., Madhani, M., Cuello, F., Charles, R. L., Brennan, J. P., Schroder, E., Browning, D. D., Eaton, P. <strong>Cysteine redox sensor in PKGI-alpha enables oxidant-induced activation.</strong> Science 317: 1393-1397, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17717153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17717153</a>] [<a href="https://doi.org/10.1126/science.1144318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17717153">Burgoyne et al. (2007)</a> concluded that this mechanism underlies cGMP-independent vasorelaxation in response to oxidants in the cardiovascular system and provides a molecular explanation for how hydrogen peroxide can operate as an endothelium-derived hyperpolarizing factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17717153" 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="#10" class="mim-tip-reference" title="Ranek, M. J., Kokkonen-Simon, K. M., Chen, A., Dunkerly-Eyring, B. L., Vera, M. P., Oeing, C. U., Patel, C. H., Nakamura, T., Zhu, G., Bedja, D., Sasaki, M., Holewinski, R. J., Van Eyk, J. E., Powell, J. D., Lee, D. I., Kass, D. A. <strong>PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress.</strong> Nature 566: 264-269, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30700906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30700906</a>] [<a href="https://doi.org/10.1038/s41586-019-0895-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30700906">Ranek et al. (2019)</a> showed that in the heart, or in isolated cardiomyocytes or fibroblasts, PKG1 phosphorylates 2 adjacent serine residues in TSC2 (<a href="/entry/191092">191092</a>) (S1365 and S1366 in mice; S1364 and S1365 in humans), which could bidirectionally control mTORC1 (see <a href="/entry/601231">601231</a>) activity stimulated by growth factors or hemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remained unchanged. PKG1 is a primary effector of nitric oxide and natriuretic peptide (see <a href="/entry/108780">108780</a>) signaling, and protects against heart disease. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knockin mice that expressed a phosphorylation-silencing mutation in TSC2 (S1365A) developed worse heart disease and had higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that could not be rescued by PKG1 stimulation. However, cardiac disease was reduced, and survival of heterozygote Tsc2(S1365A) knockin mice subjected to the same stress was improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (Tsc2(S1365E)). Resting mTORC1 activity was not altered in either knockin model. <a href="#10" class="mim-tip-reference" title="Ranek, M. J., Kokkonen-Simon, K. M., Chen, A., Dunkerly-Eyring, B. L., Vera, M. P., Oeing, C. U., Patel, C. H., Nakamura, T., Zhu, G., Bedja, D., Sasaki, M., Holewinski, R. J., Van Eyk, J. E., Powell, J. D., Lee, D. I., Kass, D. A. <strong>PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress.</strong> Nature 566: 264-269, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30700906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30700906</a>] [<a href="https://doi.org/10.1038/s41586-019-0895-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30700906">Ranek et al. (2019)</a> concluded that TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. They suggested that the serine residues identified by them provided a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30700906" 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 4 unrelated families with autosomal dominant thoracic aortic aneurysm and dissection (AAT8; <a href="/entry/615436">615436</a>), <a href="#3" class="mim-tip-reference" title="Guo, D., Regalado, E., Casteel, D. E., Santos-Cortez, R. L., Gong, L., Kim, J. J., Dyack, S., Horne, S. G., Chang, G., Jondeau, G., Boileau, C., Coselli, J. S., and 10 others. <strong>Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.</strong> Am. J. Hum. Genet. 93: 398-404, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23910461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23910461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23910461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.06.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23910461">Guo et al. (2013)</a> identified heterozygosity for a missense mutation in the PRKG1 gene (R177Q; <a href="#0001">176894.0001</a>) that segregated with disease in each family and was not found in controls. Although the mutation disrupts binding to the high-affinity cGMP binding site within the regulatory domain, R177Q mutant PRKG1 is constitutively active even in the absence of cGMP, resulting in decreased phosphorylation of the myosin regulatory light chain in fibroblasts that is predicted to cause decreased contraction of vascular smooth muscle cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23910461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Pfeifer, A., Klatt, P., Massberg, S., Ny, L., Sausbier, M., Hirneill, C., Wang, G.-X., Korth, M., Aszodi, A., Andersson, K.-E., Krombach, F., Mayerhofer, A., Ruth, P., Fassler, R., Hofmann, F. <strong>Defective smooth muscle regulation in cGMP kinase I-deficient mice.</strong> EMBO J. 17: 3045-3051, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9606187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9606187</a>] [<a href="https://doi.org/10.1093/emboj/17.11.3045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9606187">Pfeifer et al. (1998)</a> generated mice deficient in cGKI by targeted disruption. Loss of cGKI abolished nitric oxide/cGMP-dependent relaxation of smooth muscle, resulting in severe vascular and intestinal dysfunction. However, cGKI-deficient smooth muscle responded normally to cAMP, indicating that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the nitric oxide/cGMP effects in murine smooth muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9606187" 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="#2" class="mim-tip-reference" title="Foller, M., Feil, S., Ghoreschi, K., Koka, S., Gerling, A., Thunemann, M., Hofmann, F., Schuler, B., Vogel, J., Pichler, B., Kasinathan, R. S., Nicolay, J. P., Huber, S. M., Lang, F., Feil, R. <strong>Anemia and splenomegaly in cGKI-deficient mice.</strong> Proc. Nat. Acad. Sci. 105: 6771-6776, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443297</a>] [<a href="https://doi.org/10.1073/pnas.0708940105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443297">Foller et al. (2008)</a> found that cGKI deficiency in mice resulted in anemia and splenomegaly. Compared with control mice, cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with higher reticulocyte number and an increase in plasma erythropoietin (<a href="/entry/133170">133170</a>) concentration. Compared with control erythrocytes, cGKI-deficient erythrocytes exhibited in vitro a higher cytosolic Ca(2+) concentration and increased phosphatidylserine exposure, which was paralleled by faster erythrocyte clearance in vivo. <a href="#2" class="mim-tip-reference" title="Foller, M., Feil, S., Ghoreschi, K., Koka, S., Gerling, A., Thunemann, M., Hofmann, F., Schuler, B., Vogel, J., Pichler, B., Kasinathan, R. S., Nicolay, J. P., Huber, S. M., Lang, F., Feil, R. <strong>Anemia and splenomegaly in cGKI-deficient mice.</strong> Proc. Nat. Acad. Sci. 105: 6771-6776, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443297</a>] [<a href="https://doi.org/10.1073/pnas.0708940105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443297">Foller et al. (2008)</a> concluded that cGKI is a mediator of erythrocyte survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18443297" 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="#4" class="mim-tip-reference" title="Jaumann, M., Dettling, J., Gubelt, M., Zimmermann, U., Gerling, A., Paquet-Durand, F., Feil, S., Wolpert, S., Franz, C., Varakina, K., Xiong, H., Brandt, N., and 11 others. <strong>cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.</strong> Nature Med. 18: 252-259, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22270721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22270721</a>] [<a href="https://doi.org/10.1038/nm.2634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22270721">Jaumann et al. (2012)</a> found that Prkg1-null mice had a normal hearing threshold, but they were more vulnerable than wildtype mice to noise-induced hearing loss and showed markedly less recovery than wildtype mice following acoustic trauma. Prkg1 was expressed in sensory cells and neurons of the inner ear of wildtype mice, and its expression partly overlapped that of cGMP-dependent phosphodiesterase Pde5 (PDE5A; <a href="/entry/603310">603310</a>). Pharmacologic inhibition of Pde5 in wildtype mice and rats almost completely prevented noise-induced cochlear damage and caused Prkg1-dependent upregulation of poly(ADP-ribose) in hair cells and spiral ganglion. <a href="#4" class="mim-tip-reference" title="Jaumann, M., Dettling, J., Gubelt, M., Zimmermann, U., Gerling, A., Paquet-Durand, F., Feil, S., Wolpert, S., Franz, C., Varakina, K., Xiong, H., Brandt, N., and 11 others. <strong>cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.</strong> Nature Med. 18: 252-259, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22270721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22270721</a>] [<a href="https://doi.org/10.1038/nm.2634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22270721">Jaumann et al. (2012)</a> concluded that the protective effect of Prkg1 involves activation of poly(ADP-ribose) polymerase (see <a href="/entry/173870">173870</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22270721" 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 4 unrelated families with autosomal dominant thoracic aortic aneurysm and dissection (AAT8; <a href="/entry/615436">615436</a>), 1 of which had previously been described by <a href="#13" class="mim-tip-reference" title="Tran-Fadulu, V., Chen, J. H., Lemuth, D., Neichoy, B. T., Yuan, J., Gomes, N., Sparks, E., Kramer, L. A., Guo, D., Pannu, H., Braverman, A. C., Shete, S., Milewicz, D. M. <strong>Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women.</strong> Am. J. Med. Genet. 140A: 1196-1202, 2006. Note: Erratum: Am. J. Med. Genet. 140A: 1796 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16646045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16646045</a>] [<a href="https://doi.org/10.1002/ajmg.a.31236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16646045">Tran-Fadulu et al. (2006)</a> (family TAA216), <a href="#3" class="mim-tip-reference" title="Guo, D., Regalado, E., Casteel, D. E., Santos-Cortez, R. L., Gong, L., Kim, J. J., Dyack, S., Horne, S. G., Chang, G., Jondeau, G., Boileau, C., Coselli, J. S., and 10 others. <strong>Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.</strong> Am. J. Hum. Genet. 93: 398-404, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23910461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23910461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23910461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.06.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23910461">Guo et al. (2013)</a> identified heterozygosity for a c.530G-A transition in exon 3 of the PRKG1 gene, resulting in an arg177-to-gln (R177Q) substitution at a highly conserved residue in the CNB-A domain. The mutation segregated with disease in each family and was not found in 8,600 European American or 4,400 African American chromosomes in the NHLBI Exome Sequencing Project Exome Variant Server. Haplotype analysis of SNPs flanking the PRKG1 gene showed that 2 of the families (TAA508 and TAA690) shared a common haplotype in this region, but the mutation-associated haplotype was different in the other 2 families. Functional analysis using a fluorescence polarization assay demonstrated that the mutant results in a CNB-A domain that does not bind or respond to cGMP; however, transfection studies in HEK293T cells showed that the mutant was highly active in phosphotransferase activity even without cGMP, whereas wildtype protein required cGMP for activation. Patient fibroblasts showed decreased levels of phosphorylated regulatory light chain compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16646045+23910461" 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="#Osborne1997" class="mim-tip-reference" title="Osborne, K. A, Robichon, A., Burgess, E., Butland, S., Shaw, R. A., Coulthard, A., Pereira, H. S., Greenspan, R. J., Sokolowski, M. B. <strong>Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.</strong> Science 277: 834-836, 1997.">Osborne et al. (1997)</a>
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[<a href="https://doi.org/10.1126/science.1144318" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0708940105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.06.019" target="_blank">Full Text</a>]
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<strong>cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.</strong>
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[<a href="https://doi.org/10.1038/nm.2634" target="_blank">Full Text</a>]
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Li, Z., Xi, X., Gu, M., Feil, R., Ye, R. D., Eigenthaler, M., Hofmann, F., Du, X.
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<strong>A stimulatory role for cGMP-dependent protein kinase in platelet activation.</strong>
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Cell 112: 77-86, 2003.
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[<a href="https://doi.org/10.1016/s0092-8674(02)01254-0" target="_blank">Full Text</a>]
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<strong>Characterization of the human gene encoding the type I-alpha and type I-beta cGMP-dependent protein kinase (PRKG1).</strong>
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[<a href="https://doi.org/10.1006/geno.1997.4743" target="_blank">Full Text</a>]
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Orstavik, S., Sandberg, M., Berube, D., Natarajan, V., Simard, J., Walter, U., Gagne, R., Hansson, V., Jahnsen, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1544322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1544322</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1544322" 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/10.1159/000133267" target="_blank">Full Text</a>]
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<a id="Osborne1997" class="mim-anchor"></a>
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Osborne, K. A, Robichon, A., Burgess, E., Butland, S., Shaw, R. A., Coulthard, A., Pereira, H. S., Greenspan, R. J., Sokolowski, M. B.
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<strong>Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.</strong>
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Science 277: 834-836, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9242616" 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.277.5327.834" target="_blank">Full Text</a>]
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Pfeifer, A., Klatt, P., Massberg, S., Ny, L., Sausbier, M., Hirneill, C., Wang, G.-X., Korth, M., Aszodi, A., Andersson, K.-E., Krombach, F., Mayerhofer, A., Ruth, P., Fassler, R., Hofmann, F.
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[<a href="https://doi.org/10.1093/emboj/17.11.3045" target="_blank">Full Text</a>]
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Ranek, M. J., Kokkonen-Simon, K. M., Chen, A., Dunkerly-Eyring, B. L., Vera, M. P., Oeing, C. U., Patel, C. H., Nakamura, T., Zhu, G., Bedja, D., Sasaki, M., Holewinski, R. J., Van Eyk, J. E., Powell, J. D., Lee, D. I., Kass, D. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30700906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30700906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30700906" 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/s41586-019-0895-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0014-5793(89)81114-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.hyp.27.3.552" target="_blank">Full Text</a>]
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Tran-Fadulu, V., Chen, J. H., Lemuth, D., Neichoy, B. T., Yuan, J., Gomes, N., Sparks, E., Kramer, L. A., Guo, D., Pannu, H., Braverman, A. C., Shete, S., Milewicz, D. M.
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<strong>Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16646045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16646045</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16646045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31236" target="_blank">Full Text</a>]
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<a id="Yuasa2000" class="mim-anchor"></a>
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Yuasa, K., Omori, K., Yanaka, N.
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<strong>Binding and phosphorylation of a novel male germ cell-specific cGMP-dependent protein kinase-anchoring protein by cGMP-dependent protein kinase I-alpha.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10671526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10671526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10671526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.275.7.4897" target="_blank">Full Text</a>]
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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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Ada Hamosh - updated : 05/23/2019
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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 : 09/27/2013<br>Patricia A. Hartz - updated : 3/8/2012<br>Patricia A. Hartz - updated : 6/24/2008<br>Ada Hamosh - updated : 10/15/2007<br>Patricia A. Hartz - updated : 8/17/2007<br>Stylianos E. Antonarakis - updated : 1/15/2003<br>Ada Hamosh - updated : 7/20/2000<br>Rebekah S. Rasooly - updated : 5/4/1998
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</span>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/17/1991
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</span>
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</div>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/24/2019
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</span>
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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 : 05/23/2019<br>carol : 09/27/2013<br>mgross : 3/9/2012<br>terry : 3/8/2012<br>carol : 10/4/2010<br>alopez : 6/25/2008<br>terry : 6/24/2008<br>terry : 10/15/2007<br>mgross : 8/17/2007<br>ckniffin : 5/15/2003<br>mgross : 1/15/2003<br>mcapotos : 8/1/2000<br>mcapotos : 8/1/2000<br>mcapotos : 7/28/2000<br>terry : 7/20/2000<br>psherman : 6/19/1998<br>psherman : 5/4/1998<br>alopez : 6/2/1997<br>mark : 1/8/1997<br>pfoster : 9/1/1995<br>supermim : 3/16/1992<br>carol : 2/23/1992<br>carol : 9/19/1991<br>carol : 9/17/1991
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 176894
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<h3>
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<span class="mim-font">
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PROTEIN KINASE, cGMP-DEPENDENT, REGULATORY, TYPE I; PRKG1
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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cGMP-DEPENDENT PROTEIN KINASE, TYPE I, BETA; cGKI-BETA<br />
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PRKGR1B
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</span>
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</h4>
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</div>
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<br />
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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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<span class="h3 mim-font">
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cGMP-DEPENDENT PROTEIN KINASE, TYPE I, ALPHA, INCLUDED
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<span class="h4 mim-font">
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cGKI-ALPHA, INCLUDED
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</span>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PRKG1</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 10q11.23-q21.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:50,990,888-52,298,350 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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10q11.23-q21.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Aortic aneurysm, familial thoracic 8
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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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615436
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cyclic GMP and cyclic GMP-dependent protein kinase play important roles in physiologic processes such as relaxation of vascular smooth muscle and inhibition of platelet aggregation. Two main forms of cGK have been identified: a soluble form designated type I and an intrinsic membrane-bound form designated type II. Sandberg et al. (1989) isolated and characterized cDNA clones for the type I beta isozyme from human placenta libraries. </p><p>Tamura et al. (1996) cloned a human cGKI-alpha cDNA by RT-PCR of aorta RNA using primers based on the sequence of a bovine cGKI-alpha cDNA. The predicted 671-amino acid human cGKI-alpha protein is nearly identical to bovine cGKI-alpha. Based on Southern blot and sequence analyses, Tamura et al. (1996) suggested that cGKI-alpha and cGKI-beta are generated by alternative splicing of a single gene. By Northern blot analysis, cGKI-alpha was abundantly expressed as a 7.0-kb mRNA in aorta, heart, kidneys and adrenals; the 7.0-kb cGKI-beta mRNA was abundantly expressed only in the uterus. </p><p>Orstavik et al. (1997) noted that type I cGK is a homodimer, with each monomer containing a regulatory cGMP-binding domain and a catalytic domain. By Northern blot analysis, they showed that type I cGK-alpha mRNA was most abundant in lung and placenta, while type I cGK-beta was expressed at highest levels in bladder, uterus, adrenal gland, and fallopian tube. </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 Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Orstavik et al. (1997) reported that the type I cGK gene contains 19 exons spanning at least 220 kb. The first 2 exons, which the authors called 1-alpha and 1-beta, are used alternatively and encode the alpha isoform- and beta isoform-specific sequences. Orstavik et al. (1997) noted that 5 of the 7 splice sites in the Drosophila melanogaster DG2 gene, which encodes a cGK, are also present in the human type I cGK gene. They reported that levels of the DG2-encoded cGK in Drosophila affect food-search behavior and account for a naturally occurring behavioral polymorphism. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By Southern blots of human/hamster somatic cell hybrids, Orstavik et al. (1992) localized the PRKGR1B gene to chromosome 10. The gene was regionally localized to 10q11.2 by in situ hybridization. </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>By yeast 2-hybrid analysis and immunoprecipitation of mouse testis, Yuasa et al. (2000) showed that mouse Gkap42 (GKAP1; 611356) interacted with cGKI-alpha. Gcap42 was phosphorylated by cGKI-alpha in intact cells. A kinase-deficient mutant of cGKI-alpha stably associated with Gkap42, and binding of cGMP to cGKI-alpha facilitated their release from Gkap42. Yuasa et al. (2000) concluded that Gkap42 may function as an anchoring protein for cGKI-alpha and that cGKI-alpha may participate in germ cell development through phosphorylation of Golgi-associated proteins, such as GKAP42. </p><p>Li et al. (2003) showed that PRKG1 plays an important stimulatory role in platelet activation. Expression of recombinant PRKG1 in a reconstituted cell model enhanced von Willebrand factor (VWF; 613160)-induced activation of the platelet integrin alpha-IIb (607759)/beta-3 (173470). Prkg1 knockout mice showed impaired platelet responses to VWF or low doses of thrombin and prolonged bleeding time. Human platelet aggregation induced by VWF or low-dose thrombin was inhibited by PRKG1 inhibitors but enhanced by cGMP. Furthermore, a cGMP-enhancing agent, sildenafil, promoted VWF- or thrombin-induced platelet aggregation. The cGMP-stimulated platelet responses were biphasic, consisting of an initial transient stimulatory response that promoted platelet aggregation and a subsequent inhibitory response that limited the size of thrombi. </p><p>Burgoyne et al. (2007) found that the cGMP-dependent protein kinase PKG functions directly as a redox sensor. The I-alpha isoform, PKGI-alpha, formed an interprotein disulfide linking its 2 subunits in cells exposed to exogenous hydrogen peroxide. This oxidation directly activated the kinase in vitro, and in rat cells and tissues. The affinity of the kinase for substrates it phosphorylates was enhanced by disulfide formation. This oxidation-induced activation represents an alternate mechanism for regulation along with the classic activation involving nitric oxide and cGMP. Burgoyne et al. (2007) concluded that this mechanism underlies cGMP-independent vasorelaxation in response to oxidants in the cardiovascular system and provides a molecular explanation for how hydrogen peroxide can operate as an endothelium-derived hyperpolarizing factor. </p><p>Ranek et al. (2019) showed that in the heart, or in isolated cardiomyocytes or fibroblasts, PKG1 phosphorylates 2 adjacent serine residues in TSC2 (191092) (S1365 and S1366 in mice; S1364 and S1365 in humans), which could bidirectionally control mTORC1 (see 601231) activity stimulated by growth factors or hemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remained unchanged. PKG1 is a primary effector of nitric oxide and natriuretic peptide (see 108780) signaling, and protects against heart disease. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knockin mice that expressed a phosphorylation-silencing mutation in TSC2 (S1365A) developed worse heart disease and had higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that could not be rescued by PKG1 stimulation. However, cardiac disease was reduced, and survival of heterozygote Tsc2(S1365A) knockin mice subjected to the same stress was improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (Tsc2(S1365E)). Resting mTORC1 activity was not altered in either knockin model. Ranek et al. (2019) concluded that TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. They suggested that the serine residues identified by them provided a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity. </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>In 4 unrelated families with autosomal dominant thoracic aortic aneurysm and dissection (AAT8; 615436), Guo et al. (2013) identified heterozygosity for a missense mutation in the PRKG1 gene (R177Q; 176894.0001) that segregated with disease in each family and was not found in controls. Although the mutation disrupts binding to the high-affinity cGMP binding site within the regulatory domain, R177Q mutant PRKG1 is constitutively active even in the absence of cGMP, resulting in decreased phosphorylation of the myosin regulatory light chain in fibroblasts that is predicted to cause decreased contraction of vascular smooth muscle cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Pfeifer et al. (1998) generated mice deficient in cGKI by targeted disruption. Loss of cGKI abolished nitric oxide/cGMP-dependent relaxation of smooth muscle, resulting in severe vascular and intestinal dysfunction. However, cGKI-deficient smooth muscle responded normally to cAMP, indicating that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the nitric oxide/cGMP effects in murine smooth muscle. </p><p>Foller et al. (2008) found that cGKI deficiency in mice resulted in anemia and splenomegaly. Compared with control mice, cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with higher reticulocyte number and an increase in plasma erythropoietin (133170) concentration. Compared with control erythrocytes, cGKI-deficient erythrocytes exhibited in vitro a higher cytosolic Ca(2+) concentration and increased phosphatidylserine exposure, which was paralleled by faster erythrocyte clearance in vivo. Foller et al. (2008) concluded that cGKI is a mediator of erythrocyte survival. </p><p>Jaumann et al. (2012) found that Prkg1-null mice had a normal hearing threshold, but they were more vulnerable than wildtype mice to noise-induced hearing loss and showed markedly less recovery than wildtype mice following acoustic trauma. Prkg1 was expressed in sensory cells and neurons of the inner ear of wildtype mice, and its expression partly overlapped that of cGMP-dependent phosphodiesterase Pde5 (PDE5A; 603310). Pharmacologic inhibition of Pde5 in wildtype mice and rats almost completely prevented noise-induced cochlear damage and caused Prkg1-dependent upregulation of poly(ADP-ribose) in hair cells and spiral ganglion. Jaumann et al. (2012) concluded that the protective effect of Prkg1 involves activation of poly(ADP-ribose) polymerase (see 173870). </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>1 Selected Example):</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 AORTIC ANEURYSM, FAMILIAL THORACIC 8</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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PRKG1, ARG177GLN
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<br />
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SNP: rs397515330,
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ClinVar: RCV000055667, RCV000494178, RCV002311000
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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 4 unrelated families with autosomal dominant thoracic aortic aneurysm and dissection (AAT8; 615436), 1 of which had previously been described by Tran-Fadulu et al. (2006) (family TAA216), Guo et al. (2013) identified heterozygosity for a c.530G-A transition in exon 3 of the PRKG1 gene, resulting in an arg177-to-gln (R177Q) substitution at a highly conserved residue in the CNB-A domain. The mutation segregated with disease in each family and was not found in 8,600 European American or 4,400 African American chromosomes in the NHLBI Exome Sequencing Project Exome Variant Server. Haplotype analysis of SNPs flanking the PRKG1 gene showed that 2 of the families (TAA508 and TAA690) shared a common haplotype in this region, but the mutation-associated haplotype was different in the other 2 families. Functional analysis using a fluorescence polarization assay demonstrated that the mutant results in a CNB-A domain that does not bind or respond to cGMP; however, transfection studies in HEK293T cells showed that the mutant was highly active in phosphotransferase activity even without cGMP, whereas wildtype protein required cGMP for activation. Patient fibroblasts showed decreased levels of phosphorylated regulatory light chain compared to controls. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
|
|
Osborne et al. (1997)
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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>REFERENCES</strong>
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</span>
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</h4>
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