3881 lines
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Entry
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- *600734 - POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600734</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600734">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li 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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</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=ENSG00000120457;t=ENST00000529694" 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=3762" 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=600734" 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=ENSG00000120457;t=ENST00000529694" 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_000890,NM_001354169,XM_011542810" 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_000890" 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=600734" 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=09010&isoform_id=09010_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/KCNJ5" 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/619879,976203,1055026,1890046,24797141,46854375,46854401,46854839,46854847,50960091,50960800,67677839,119588130,119588131,189053525,296434543,378406353,378406355,380861867,767970123,1229732672,1751376242,2402697928,2462525103" 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/P48544" 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=3762" 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=ENSG00000120457;t=ENST00000529694" 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=KCNJ5" 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=KCNJ5" 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+3762" 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/KCNJ5" 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:3762" 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/3762" 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=chr11&hgg_gene=ENST00000529694.6&hgg_start=128891356&hgg_end=128921163&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:6266" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/kcnj5" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600734[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=600734[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/ENSG00000120457" 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=KCNJ5" 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=KCNJ5" 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=KCNJ5" 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=KCNJ5&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/PA216" 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:6266" 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/FBgn0265042.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:104755" 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/KCNJ5#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:104755" 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/3762/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=3762" 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=WBGene00002149;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00002149 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00002150;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00002150 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-120215-97" 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:3762" 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=KCNJ5&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703234002<br />
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">ICD+</a>
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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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600734
|
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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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POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CARDIAC INWARD RECTIFIER; CIR<br />
|
|
G PROTEIN-ACTIVATED INWARDLY RECTIFYING POTASSIUM CHANNEL 4; GIRK4<br />
|
|
INWARDLY RECTIFYING POTASSIUM CHANNEL KIR3.4<br />
|
|
KATP1
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KCNJ5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KCNJ5</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">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/1085?start=-3&limit=10&highlight=1085">11q24.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:128891356-128921163&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'})">11:128,891,356-128,921,163</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613677,613485" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/1085?start=-3&limit=10&highlight=1085">
|
|
11q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hyperaldosteronism, familial, type III
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613677"> 613677 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
|
</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Long QT syndrome 13
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613485"> 613485 </a>
|
|
|
|
</span>
|
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<p>G protein-sensitive inwardly rectifying potassium channels, such as KCNJ5, are activated through direct interactions of their cytoplasmic N and C termini with the beta (see GNB1; <a href="/entry/139380">139380</a>)-gamma (see GNG2; <a href="/entry/606981">606981</a>) subunits of G proteins. KCNJ proteins contain 2 transmembrane domains that surround the P region, which harbors the potassium ion selectivity filter. KCNJ5 can pair with KCNJ3 (<a href="/entry/601534">601534</a>) to form a highly active heteromultimer, or it can form a low to moderately active homomultimer (<a href="#7" class="mim-tip-reference" title="He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., Logothetis, D. E. <strong>Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the beta-gamma subunits of G proteins.</strong> J. Biol. Chem. 277: 6088-6096, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741896</a>] [<a href="https://doi.org/10.1074/jbc.M104851200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741896">He et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741896" 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="#1" class="mim-tip-reference" title="Ashford, M. L. J., Bond, C. T., Blair, T. A., Adelman, J. P. <strong>Cloning and functional expression of a rat heart KATP channel.</strong> Nature 370: 456-459, 1994. Note: Retraction: Nature 378: 792 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8047164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8047164</a>] [<a href="https://doi.org/10.1038/370456a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8047164">Ashford et al. (1994)</a> cloned rat Kcnj5 and isolated the human homolog. <a href="#16" class="mim-tip-reference" title="Tucker, S. J., James, M. R., Adelman, J. P. <strong>Assignment of K(ATP)-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24.</strong> Genomics 28: 127-128, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590741</a>] [<a href="https://doi.org/10.1006/geno.1995.1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590741">Tucker et al. (1995)</a> noted that the primary structure of KCNJ5 placed it in the J subfamily of inwardly rectifying potassium channels (<a href="#2" class="mim-tip-reference" title="Bond, C. T., Pessia, M., Xia, X.-M., Lagrutta, A., Kavanaugh, M. P., Adelman, J. P. <strong>Cloning and expression of a family of inward rectifier potassium channels.</strong> Receptors Channels 2: 183-191, 1994. Note: Erratum: Receptors Channels 2: following 350, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874445</a>]" pmid="7874445">Bond et al., 1994</a>), which includes KCNJ2 (<a href="/entry/600681">600681</a>) and KCNJ4 (<a href="/entry/600504">600504</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7590741+8047164+7874445" 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="#17" class="mim-tip-reference" title="Wickman, K., Seldin, M. F., Gendler, S. J., Clapham, D. E. <strong>Partial structure, chromosome localization, and expression of the mouse Girk4 gene.</strong> Genomics 40: 395-401, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9073506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9073506</a>] [<a href="https://doi.org/10.1006/geno.1997.4599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9073506">Wickman et al. (1997)</a> cloned the mouse Girk4 gene and reported a partial sequence of human GIRK4. They showed that Girk4 was expressed almost exclusively in mouse heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9073506" 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="#14" class="mim-tip-reference" title="Perry, C. A., Pravetoni, M., Teske, J. A., Aguado, C., Erickson, D. J., Medrano, J. F., Lujan, R., Kotz, C. M., Wickman, K. <strong>Predisposition to late-onset obesity in GIRK4 knockout mice.</strong> Proc. Nat. Acad. Sci. 105: 8148-8153, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18523006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18523006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18523006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803261105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18523006">Perry et al. (2008)</a> identified prominent Girk4 expression mouse hypothalamus, with most pronounced expression in the ventromedial, paraventricular, and arcuate nuclei, neuron populations implicated in energy homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18523006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using atrial and endocardial left ventricular tissue samples from 4 patients undergoing cardiac valve surgery, <a href="#18" class="mim-tip-reference" title="Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H. B., Ellinor, P. T., Gao, L., Lin, X., Li, L., and 9 others. <strong>Identification of a Kir3.4 mutation in congenital long QT syndrome.</strong> Am. J. Hum. Genet. 86: 872-880, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20560207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20560207</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20560207">Yang et al. (2010)</a> demonstrated by Western blotting that Kir3.4 is expressed in human atria and ventricles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20560207" 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="Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P. <strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong> Neurology 82: 1058-1064, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24574546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24574546</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24574546">Kokunai et al. (2014)</a> found significant expression of the KCNJ5 gene in human skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24574546" 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>By PCR screening of somatic cell hybrids, radiation hybrids, and YACs, <a href="#16" class="mim-tip-reference" title="Tucker, S. J., James, M. R., Adelman, J. P. <strong>Assignment of K(ATP)-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24.</strong> Genomics 28: 127-128, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590741</a>] [<a href="https://doi.org/10.1006/geno.1995.1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590741">Tucker et al. (1995)</a> mapped the KCNJ5 gene to chromosome 11q24, approximately 500 kb telomeric to the Friend leukemia virus integration site (<a href="/entry/193067">193067</a>). Using human/rodent somatic cell hybrids, <a href="#17" class="mim-tip-reference" title="Wickman, K., Seldin, M. F., Gendler, S. J., Clapham, D. E. <strong>Partial structure, chromosome localization, and expression of the mouse Girk4 gene.</strong> Genomics 40: 395-401, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9073506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9073506</a>] [<a href="https://doi.org/10.1006/geno.1997.4599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9073506">Wickman et al. (1997)</a> localized the human KCNJ5 gene to chromosome 11, consistent with previous studies that localized the gene to 11q23-ter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7590741+9073506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using interspecific backcross analysis, <a href="#17" class="mim-tip-reference" title="Wickman, K., Seldin, M. F., Gendler, S. J., Clapham, D. E. <strong>Partial structure, chromosome localization, and expression of the mouse Girk4 gene.</strong> Genomics 40: 395-401, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9073506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9073506</a>] [<a href="https://doi.org/10.1006/geno.1997.4599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9073506">Wickman et al. (1997)</a> mapped the mouse Girk4 gene to chromosome 9, consistent with the mapping of human GIRK4 to chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9073506" 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="#1" class="mim-tip-reference" title="Ashford, M. L. J., Bond, C. T., Blair, T. A., Adelman, J. P. <strong>Cloning and functional expression of a rat heart KATP channel.</strong> Nature 370: 456-459, 1994. Note: Retraction: Nature 378: 792 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8047164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8047164</a>] [<a href="https://doi.org/10.1038/370456a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8047164">Ashford et al. (1994)</a> reported that rat Kcnj5 exhibited all the essential features of native cardiac ATP-sensitive potassium (KATP) channels when expressed in various cell lines. However, <a href="#11" class="mim-tip-reference" title="Krapivinsky, G., Gordon, E. A., Wickman, K., Velimirovic, B., Krapivinsky, L., Clapham, D. E. <strong>The G-protein-gated atrial K+ channel I-KACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.</strong> Nature 374: 135-141, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7877685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7877685</a>] [<a href="https://doi.org/10.1038/374135a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7877685">Krapivinsky et al. (1995)</a> found that rat Kcnj5, which they called Cir, formed a unique potassium channel when expressed in multiple cell lines, but it did not constitute KATP by itself. They demonstrated that coexpression of Kcnj5 with Girk1 (KCNJ3) resulted in a significantly increased G protein-gated inwardly rectifying potassium current that showed properties similar to those of the atrial potassium channel IKACh, which is involved in acetylcholine (ACh)-dependent slowing of the heart rate. <a href="#11" class="mim-tip-reference" title="Krapivinsky, G., Gordon, E. A., Wickman, K., Velimirovic, B., Krapivinsky, L., Clapham, D. E. <strong>The G-protein-gated atrial K+ channel I-KACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.</strong> Nature 374: 135-141, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7877685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7877685</a>] [<a href="https://doi.org/10.1038/374135a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7877685">Krapivinsky et al. (1995)</a> proposed that atrial IKACh is a heteromultimer composed of GIRK1 and CIR. Subsequently, <a href="#1" class="mim-tip-reference" title="Ashford, M. L. J., Bond, C. T., Blair, T. A., Adelman, J. P. <strong>Cloning and functional expression of a rat heart KATP channel.</strong> Nature 370: 456-459, 1994. Note: Retraction: Nature 378: 792 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8047164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8047164</a>] [<a href="https://doi.org/10.1038/370456a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8047164">Ashford et al. (1994)</a> issued a retraction stating that they could not replicate their findings suggesting that Kcnj5 encodes a subunit of cardiac KATP channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8047164+7877685" 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="Corey, S., Clapham, D. E. <strong>Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers.</strong> J. Biol. Chem. 273: 27499-27504, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9765280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9765280</a>] [<a href="https://doi.org/10.1074/jbc.273.42.27499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9765280">Corey and Clapham (1998)</a> found that only about half of the Girk4 purified from bovine atria was associated with Girk1 in a heterotetramer, whereas the remaining Girk4 formed a high molecular mass, SDS-resistant complex lacking Girk1. They noted that recombinant Girk4 homomultimers had been shown to produce large whole cell currents with long single channel open times (<a href="#8" class="mim-tip-reference" title="Ji, S., John, S. A., Lu, Y., Weiss, J. N. <strong>Mechanosensitivity of the cardiac muscarinic potassium channel: a novel property conferred by Kir3.4 subunit.</strong> J. Biol. Chem. 273: 1324-1328, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9430664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9430664</a>] [<a href="https://doi.org/10.1074/jbc.273.3.1324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9430664">Ji et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9430664+9765280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an extracellular epitope tag on rat Girk1, <a href="#9" class="mim-tip-reference" title="Kennedy, M. E., Nemec, J., Corey, S., Wickman, K., Clapham, D. E. <strong>GIRK4 confers appropriate processing and cell surface localization to G-protein-gated potassium channels.</strong> J. Biol. Chem. 274: 2571-2582, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9891030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9891030</a>] [<a href="https://doi.org/10.1074/jbc.274.4.2571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9891030">Kennedy et al. (1999)</a> demonstrated that Girk1 required association with Girk4 for cell surface localization. Girk4 associated with Girk1 during or shortly after subunit synthesis and allowed appropriate glycosylation of the Girk1 subunit to a form seen in native atrial tissue. The C terminus of Girk4 was required for cell surface localization. Girk1 appeared intracellular in atrial myocytes isolated from Girk4-knockout mice, and it was not maturely glycosylated, supporting an essential role for GIRK4 in processing and cell surface localization of GIRK1/GIRK4 channels in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9891030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using biochemical and electrophysiologic approaches, <a href="#7" class="mim-tip-reference" title="He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., Logothetis, D. E. <strong>Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the beta-gamma subunits of G proteins.</strong> J. Biol. Chem. 277: 6088-6096, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741896</a>] [<a href="https://doi.org/10.1074/jbc.M104851200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741896">He et al. (2002)</a> found that his64 and leu268 mediated human GIRK4 activity and that mutation of these sites significantly reduced binding of GIRK4 to G-beta-gamma dimers. In GIRK4/GIRK1 heterodimers, his64 and leu268 in GIRK4 contributed more to G protein sensitivity than did the corresponding his57 and leu262 residues of GIRK1. Mutation of these residues in GIRK4 or GIRK1 abolished all G protein-mediated currents. <a href="#7" class="mim-tip-reference" title="He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., Logothetis, D. E. <strong>Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the beta-gamma subunits of G proteins.</strong> J. Biol. Chem. 277: 6088-6096, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741896</a>] [<a href="https://doi.org/10.1074/jbc.M104851200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741896">He et al. (2002)</a> stated that mutation of leu339 in GIRK4 or leu333 in GIRK1 abolished agonist-induced G protein-mediated currents, but not agonist-independent G protein-mediated currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Long QT Syndrome</em></strong></p><p>
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In a large 4-generation Chinese family with autosomal dominant long QT syndrome mapping to chromosome 11q23.3-q23.4 (LQT13; <a href="/entry/613485">613485</a>), <a href="#18" class="mim-tip-reference" title="Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H. B., Ellinor, P. T., Gao, L., Lin, X., Li, L., and 9 others. <strong>Identification of a Kir3.4 mutation in congenital long QT syndrome.</strong> Am. J. Hum. Genet. 86: 872-880, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20560207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20560207</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20560207">Yang et al. (2010)</a> sequenced the candidate gene KCNJ5 and identified heterozygosity for a missense mutation (G387R; <a href="#0001">600734.0001</a>) in affected individuals. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies demonstrated that the mutation has a dominant-negative effect that results in near-complete loss of channel activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20560207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Hyperaldosteronism Type III</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P. <strong>K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.</strong> Science 331: 768-772, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21311022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21311022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21311022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1198785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21311022">Choi et al. (2011)</a> identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5 present in 8 of 22 human aldosterone-producing adrenal adenomas: G151R (<a href="#0004">600734.0004</a>) and L168R. In addition, <a href="#5" class="mim-tip-reference" title="Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P. <strong>K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.</strong> Science 331: 768-772, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21311022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21311022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21311022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1198785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21311022">Choi et al. (2011)</a> identified heterozygosity for a missense mutation in KCNJ5 (T158A; <a href="#0002">600734.0002</a>) in a family segregating autosomal dominant hyperaldosteronism type III (HALD3; <a href="/entry/613677">613677</a>). This mutation caused increased sodium conductance and severe aldosteronism and massive bilateral adrenal hyperplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21311022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Italian mother and daughter with primary aldosteronism, <a href="#12" class="mim-tip-reference" title="Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others. <strong>KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.</strong> Hypertension 59: 235-240, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22203740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22203740</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.111.183996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22203740">Mulatero et al. (2012)</a> identified heterozygosity for a missense mutation in the KCNJ5 gene (G151E; <a href="#0005">600734.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22203740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a mother and daughter with severe aldosteronism requiring total adrenalectomy, <a href="#4" class="mim-tip-reference" title="Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D. A., Hatch, M. M., Hurt, D. E., Lin, L., Xekouki, P., Stratakis, C. A., Chrousos, G. P. <strong>A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension.</strong> J. Clin. Endocr. Metab. 97: E1532-E1539, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22628607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22628607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22628607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2012-1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22628607">Charmandari et al. (2012)</a> identified heterozygosity for a missense mutation in the KCNJ5 gene (I157S; <a href="#0006">600734.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22628607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M. <strong>Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.</strong> Hypertension 63: 783-789, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24420545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24420545</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.113.02234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24420545">Murthy et al. (2014)</a> analyzed the KCNJ5 gene in 251 patients with apparent sporadic florid primary aldosteronism, and identified 3 heterozygous missense mutations, G247R (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200170681;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs200170681</a>; <a href="#0003">600734.0003</a>), E246K (<a href="#0007">600734.0007</a>), and R52H (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144062083;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144062083</a>). In addition, 12 (5%) of the 251 patients carried the rare SNP E282Q (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7102584;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7102584</a>), present in a population frequency of 2% in the 1000 Genomes cohort. Although remote from the KCNJ5 selectivity filter, 3 of the 4 variants (E246K, R52H, and E282Q) were shown to alter inward rectification, conduction of Na+ currents, and angiotensin II (<a href="/entry/106150">106150</a>)-induced aldosterone release in the H295R cell line, a well-established model for the human zona glomerulosa cell. Results of electrophysiologic analysis of the G247R channel, however, were indistinguishable from those of the wildtype channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24420545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 4 unrelated families with early-onset primary hyperaldosteronism, <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> identified heterozygosity for missense mutations in the KCNJ5 gene: G151R in 2 families with severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control, and G151E in 2 families that had more easily controlled hypertension and no evidence of adrenal hyperplasia. Electrophysiologic analysis demonstrated that although both mutations alter the K+ selectivity of the channel, the G151E mutation causes much greater Na+ conductance than G151R, resulting in rapid Na(+)-dependent cell lethality. <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> proposed that the increased lethality associated with the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus paradoxically resulting in a milder phenotype in those patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22308486" 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="#14" class="mim-tip-reference" title="Perry, C. A., Pravetoni, M., Teske, J. A., Aguado, C., Erickson, D. J., Medrano, J. F., Lujan, R., Kotz, C. M., Wickman, K. <strong>Predisposition to late-onset obesity in GIRK4 knockout mice.</strong> Proc. Nat. Acad. Sci. 105: 8148-8153, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18523006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18523006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18523006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803261105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18523006">Perry et al. (2008)</a> showed that Girk4-null mice were predisposed to late-onset obesity (<a href="/entry/601665">601665</a>). By 9 months, Girk4-null mice were approximately 25% heavier than wildtype controls due to greater body fat. Before the development of overweight, Girk4-null mice exhibited a tendency toward greater food intake and an increased propensity to work for food in an operant task. Girk4-null mice also exhibited reduced net energy expenditure, despite displaying elevated resting heart rates and core body temperatures. These data implicated GIRK4-containing channels in signaling crucial to energy homeostasis and body weight. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18523006" 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 id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>7 Selected Examples</a>):</strong>
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<a href="/allelicVariants/600734" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600734[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199830292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199830292;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199830292?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199830292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199830292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009405 OR RCV000193019 OR RCV000312115 OR RCV000865749 OR RCV003162221" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009405, RCV000193019, RCV000312115, RCV000865749, RCV003162221" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009405...</a>
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<p>In affected members of a large 4-generation Chinese family with autosomal dominant long QT syndrome (LQT13; <a href="/entry/613485">613485</a>), <a href="#18" class="mim-tip-reference" title="Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H. B., Ellinor, P. T., Gao, L., Lin, X., Li, L., and 9 others. <strong>Identification of a Kir3.4 mutation in congenital long QT syndrome.</strong> Am. J. Hum. Genet. 86: 872-880, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20560207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20560207</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20560207">Yang et al. (2010)</a> identified heterozygosity for a 1473C-G transversion in the KCNJ5 gene, resulting in a gly387-to-arg (G387R) substitution at a highly conserved residue. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies in HEK293 cells cotransfected with Kir3.4 and Kir3.1 (KCNJ3; <a href="/entry/601534">601534</a>) demonstrated that the mutant has a dominant-negative effect resulting in drastic reduction of inward currents compared to wildtype. In addition, plasma membrane and intracellular expression levels of Kir3.4 and Kir3.1 were markedly reduced in HEK293 cells cotransfected with the mutation compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20560207" 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="Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P. <strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong> Neurology 82: 1058-1064, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24574546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24574546</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24574546">Kokunai et al. (2014)</a> identified a heterozygous G387R mutation in a 35-year-old Japanese man who developed periodic muscle paralysis associated with reduced serum potassium concentrations beginning at age 31 years. He had no cardiac symptoms, but ECG showed possible sinus arrest during the attacks and prominent U waves at normal potassium concentrations. Although <a href="#10" class="mim-tip-reference" title="Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P. <strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong> Neurology 82: 1058-1064, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24574546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24574546</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24574546">Kokunai et al. (2014)</a> suggested that the phenotype resembled Andersen-Tawil syndrome (<a href="/entry/170390">170390</a>), the patient did not have dysmorphic features. There was a strong family history of significant cardiac arrhythmia, but neither detailed clinical features nor DNA from family members was available. The patient did not have increased serum aldosterone. The mutation, which was found by exome capture resequencing analysis of 162 genes encoding ion channels and confirmed by Sanger sequencing, was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. In vitro functional expression studies in Xenopus oocytes showed that coexpression of KCNJ2 (<a href="/entry/600681">600681</a>) with mutant KCNJ5 significantly reduced the inwardly rectifying potassium current compared to that observed with coexpression of KCNJ2 with wildtype KCNJ5. <a href="#10" class="mim-tip-reference" title="Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P. <strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong> Neurology 82: 1058-1064, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24574546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24574546</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24574546">Kokunai et al. (2014)</a> concluded that the reduction in this current caused by loss of function of KCNJ2 is the underlying cause of periodic paralysis and cardiac conduction abnormalities in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24574546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 HYPERALDOSTERONISM, FAMILIAL, TYPE III</strong>
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ALDOSTERONE-PRODUCING ADRENAL ADENOMA, SOMATIC, INCLUDED
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KCNJ5, THR158ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906778 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906778;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023035 OR RCV000122747 OR RCV000194572" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023035, RCV000122747, RCV000194572" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023035...</a>
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<p><strong><em>Familial Hyperaldosteronism Type III</em></strong></p><p>
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In a father and 2 daughters with hyperaldosteronism type III (HALD3; <a href="/entry/613677">613677</a>), <a href="#5" class="mim-tip-reference" title="Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P. <strong>K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.</strong> Science 331: 768-772, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21311022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21311022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21311022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1198785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21311022">Choi et al. (2011)</a> identified heterozygosity for an A-to-G transition in the KCNJ5 gene resulting in a threonine-to-alanine substitution at codon 158 (T158A). This mutation was present in affected family members and was not identified in 900 control alleles. All 3 patients had massive adrenal hyperplasia and required bilateral adrenalectomy in childhood. Threonine-158 is conserved among KCNJ5 orthologs and other inward rectifiers and lies in the loop between the selectivity filter and the second transmembrane domain. The T158A mutation eliminates hydrogen bonds that constrain the structure of the KCNJ5 potassium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21311022" 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="Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P. <strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong> Neurology 82: 1058-1064, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24574546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24574546</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24574546">Kokunai et al. (2014)</a> identified a T158A mutation in a patient with prolonged QU on ECG recorded at normal potassium concentration who developed a hypokalemic paralytic attack and primary aldosteronism 2 years later. The patient was 1 of 21 Japanese patients with a phenotype resembling Andersen-Tawil syndrome (<a href="/entry/170390">170390</a>) who did not carry a mutation in the KCNJ2 gene (<a href="/entry/600681">600681</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24574546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Aldosterone-Producing Adrenal Adenoma</em></strong></p><p>
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In an aldosterone-producing adrenal adenoma from an Italian patient with primary aldosteronism, <a href="#12" class="mim-tip-reference" title="Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others. <strong>KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.</strong> Hypertension 59: 235-240, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22203740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22203740</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.111.183996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22203740">Mulatero et al. (2012)</a> identified a somatic c.472A-G transition, resulting in a thr158-to-ala (T158A) mutation in the KCNJ5 gene. The mutation was not present in germline DNA from peripheral blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22203740" 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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KCNJ5, GLY247ARG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200170681;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs200170681</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200170681 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200170681;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs200170681?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs200170681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs200170681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000122748 OR RCV001084390 OR RCV002381433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122748, RCV001084390, RCV002381433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122748...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to atrial fibrillation or hyperaldosteronism has not been confirmed.</p><p><a href="#3" class="mim-tip-reference" title="Calloe, K., Ravn, L. S., Schmitt, N., Sui, J. L., Duno, M., Haunso, S., Grunnet, M., Svendsen, J. H., Olesen, S.-P. <strong>Characterizations of a loss-of-function mutation in the Kir3.4 channel subunit.</strong> Biochem. Biophys. Res. Commun. 364: 889-895, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17967416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17967416</a>] [<a href="https://doi.org/10.1016/j.bbrc.2007.10.106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17967416">Calloe et al. (2007)</a> analyzed the candidate gene KCNJ5 in 158 patients with documented atrial fibrillation (AF; see <a href="/entry/608583">608583</a>) followed by restored sinus rhythm, and identified a 69-year-old woman who had a single episode of AF that spontaneously reverted after 3 days; she was heterozygous for a 739G-A transition, resulting in a gly247-to-arg (G247R) substitution at a highly conserved residue in the cytoplasmic region of the Kir3.4 C terminus. The mutation was also detected in heterozygosity in her unaffected 48-year-old son, but was not found in her 4 other sons, in 96 controls, or in the PharmGKB or NCBI SNP databases. The patient was negative for mutation in 8 other known AF-associated genes. Functional analysis in Xenopus oocytes showed reduction of basal current with the G247R mutant compared to wildtype, and coexpression with the muscarinic acetylcholine receptor type 2 (CHRM2; <a href="/entry/118493">118493</a>) showed a severe decrease in acetylcholine-induced current, indicating that the G247R mutant interferes with activation by the stimulatory G-beta-gamma subunits. Coexpression with wildtype Kir3.4 or Kir3.1 (KCNJ3; <a href="/entry/601534">601534</a>) channels had a compensating effect on both basal current levels and the response to muscarinic stimulation, suggesting that function of Kir3.4-G247R is compensated in vivo, which <a href="#3" class="mim-tip-reference" title="Calloe, K., Ravn, L. S., Schmitt, N., Sui, J. L., Duno, M., Haunso, S., Grunnet, M., Svendsen, J. H., Olesen, S.-P. <strong>Characterizations of a loss-of-function mutation in the Kir3.4 channel subunit.</strong> Biochem. Biophys. Res. Commun. 364: 889-895, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17967416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17967416</a>] [<a href="https://doi.org/10.1016/j.bbrc.2007.10.106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17967416">Calloe et al. (2007)</a> proposed might explain the lack of clear clinical manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17967416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M. <strong>Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.</strong> Hypertension 63: 783-789, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24420545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24420545</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.113.02234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24420545">Murthy et al. (2014)</a> identified the G247R mutation in a woman who was diagnosed at 38 years of age with florid primary aldosteronism (see <a href="/entry/613677">613677</a>). However, electrophysiologic studies in Xenopus oocytes showed that a high-Na+ bath solution did not alter the resting potential of the G247R channel, and permeability of the mutant channel was similar to wildtype in high-K+ or high-Na+ bath solutions, exhibiting typical inward rectification in the former and almost no measurable current in the latter. Functional analysis in transiently transfected H295R cells demonstrated that G247R behaved indistinguishably from wildtype, showing no change in basal or angiotensin II (<a href="/entry/106150">106150</a>)-induced aldosterone release. <a href="#13" class="mim-tip-reference" title="Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M. <strong>Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.</strong> Hypertension 63: 783-789, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24420545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24420545</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.113.02234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24420545">Murthy et al. (2014)</a> concluded that the patient's aldosteronism had another cause. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24420545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386352319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386352319;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs386352319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs386352319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000122472 OR RCV000122749 OR RCV000122750 OR RCV002326795 OR RCV003531964" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122472, RCV000122749, RCV000122750, RCV002326795, RCV003531964" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122472...</a>
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<p><strong><em>Aldosterone-Producing Adrenal Adenoma</em></strong></p><p>
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In 2 of 22 aldosterone-producing adrenal adenomas (APAs) from unrelated patients with primary hyperaldosteronism (<a href="/entry/613677">613677</a>), <a href="#5" class="mim-tip-reference" title="Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P. <strong>K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.</strong> Science 331: 768-772, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21311022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21311022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21311022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1198785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21311022">Choi et al. (2011)</a> identified a somatic G-to-A transition at position chr11:126,286,829 in the KCNJ5 gene, resulting in a gly151-to-arg (G151R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21311022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an APA from a patient from Wurzburg with primary hyperaldosteronism, <a href="#12" class="mim-tip-reference" title="Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others. <strong>KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.</strong> Hypertension 59: 235-240, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22203740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22203740</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.111.183996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22203740">Mulatero et al. (2012)</a> identified a somatic KCNJ5 G151R mutation. The mutation was not present in germline DNA from peripheral blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22203740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Hyperaldosteronism Type III</em></strong></p><p>
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In affected individuals from 2 unrelated families with early-onset hyperaldosteronism (HALD3; <a href="/entry/613677">613677</a>), <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> identified heterozygosity for a 451G-A transition in the KCNJ5 gene, resulting in the G151R substitution. The mutation was not found in unaffected family members or in 6,000 control chromosomes. Patients carrying the G151R mutation had severe, spironolactone-unresponsive aldosteronism that worsened with age and required bilateral adrenalectomy. <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> stated that somatic G151R mutations had previously been detected in 86 aldosterone-producing adenomas (23% of all APAs). Electrophysiologic analysis in transfected mammalian 293T cells demonstrated that the G151R mutation results in increased Na+ conductance, although to a lesser extent than G151E (<a href="/entry/600743#0005">600743.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22308486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HYPERALDOSTERONISM, FAMILIAL, TYPE III</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777437 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777437;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777437?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000122751 OR RCV001210015" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122751, RCV001210015" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122751...</a>
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<p>In an Italian mother and daughter with primary hyperaldosteronism (HALD3; <a href="/entry/613677">613677</a>), <a href="#12" class="mim-tip-reference" title="Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others. <strong>KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.</strong> Hypertension 59: 235-240, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22203740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22203740</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.111.183996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22203740">Mulatero et al. (2012)</a> identified heterozygosity for a c.452G-A transition in the KCNJ5 gene, resulting in a gly151-to-glu (G151E) substitution at a conserved residue in the selectivity filter. Electrophysiologic analysis in transfected HEK cells revealed that the mutant channel is no longer K+ selective but is similarly permeable to Na+ and K+. Both patients had normal-appearing adrenal glands by CT scan, and their symptoms were controlled by medication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22203740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected individuals from 2 unrelated families with early-onset hyperaldosteronism, <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> identified heterozygosity for the G151E substitution in the KCNJ5 gene. The mutation was not found in unaffected family members or in 6,000 control chromosomes. Patients carrying the G151E mutation had remarkable responsiveness to spironolactone and did not require adrenalectomy; in 1 G151E carrier who underwent adrenalectomy before availability of spironolactone, adrenal histology was reported as normal. <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> noted that in contrast to the G151R mutation (<a href="#0004">600734.0004</a>), G151E had not been observed in adrenal adenomas, suggesting that G151E cannot support development of increased adrenal cell mass. Electrophysiologic analysis in transfected mammalian 293T cells demonstrated that the G151E mutation results in much greater Na+ conductance than G151R, leading to rapid Na(+)-dependent cell lethality. <a href="#15" class="mim-tip-reference" title="Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. <strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong> Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308486">Scholl et al. (2012)</a> suggested that the increased lethality of the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus resulting in a milder phenotype in those patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22308486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 HYPERALDOSTERONISM, FAMILIAL, TYPE III</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777438 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777438;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000122752" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122752" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122752</a>
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<p>In a mother and daughter with severe hyperaldosteronism (HALD3; <a href="/entry/613677">613677</a>) requiring total adrenalectomy, <a href="#4" class="mim-tip-reference" title="Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D. A., Hatch, M. M., Hurt, D. E., Lin, L., Xekouki, P., Stratakis, C. A., Chrousos, G. P. <strong>A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension.</strong> J. Clin. Endocr. Metab. 97: E1532-E1539, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22628607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22628607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22628607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2012-1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22628607">Charmandari et al. (2012)</a> identified heterozygosity for a 470G-T transversion in the KCNJ5 gene, resulting in an ile157-to-ser (I157S) substitution at a highly conserved residue at the C-terminal end of the loop leading away from the selectivity filter. Whole-cell voltage clamp recordings in HEK293T cells coexpressing Kir3.4 and Kir3.1 (KCNJ3; <a href="/entry/601534">601534</a>) channels demonstrated loss of channel selectivity and less negative reversal potentials with I157S mutant Kir3.4 compared to wildtype. <a href="#4" class="mim-tip-reference" title="Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D. A., Hatch, M. M., Hurt, D. E., Lin, L., Xekouki, P., Stratakis, C. A., Chrousos, G. P. <strong>A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension.</strong> J. Clin. Endocr. Metab. 97: E1532-E1539, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22628607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22628607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22628607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2012-1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22628607">Charmandari et al. (2012)</a> concluded that mutations near the channel pore result in loss of K+ selectivity and increased Na+ conductance, resulting in increased cell membrane depolarization, increased Ca2+ entry into adrenal glomerulosa cells, and increased aldosterone synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22628607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777439 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777439;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777439?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000122753" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122753" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122753</a>
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<p>In a woman who was diagnosed at 37 years of age with primary hyperaldosteronism (HALD3; <a href="/entry/613677">613677</a>) and who had bilateral adrenal hyperplasia diagnosed by CT scan and adrenal vein sampling, <a href="#13" class="mim-tip-reference" title="Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M. <strong>Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.</strong> Hypertension 63: 783-789, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24420545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24420545</a>] [<a href="https://doi.org/10.1161/HYPERTENSIONAHA.113.02234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24420545">Murthy et al. (2014)</a> identified heterozygosity for a c.736G-A transition in the KCNJ5 gene, resulting in a glu246-to-lys (E246K) substitution at a highly conserved residue. Electrophysiologic studies in Xenopus oocytes showed significant depolarization of the E246K channel in a high-Na+ bath solution, with no clear rectification of the mutant channel in a high-K+ bath solution; switching from a high-K+ to a high-Na+ bath solution showed virtually no change in the I-V curve, confirming a substantial loss of K+ selectivity in the mutant channel. Functional analysis in transiently transfected H295R cells demonstrated a 2- to 3-fold increase in angiotensin II (<a href="/entry/106150">106150</a>)-induced aldosterone release with the E246K mutant compared to wildtype. In addition, H295R cells transfected with the E246K mutant showed significantly reduced viability after 48 hours of culture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24420545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Ashford1994" class="mim-anchor"></a>
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Ashford, M. L. J., Bond, C. T., Blair, T. A., Adelman, J. P.
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<strong>Cloning and functional expression of a rat heart KATP channel.</strong>
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Nature 370: 456-459, 1994. Note: Retraction: Nature 378: 792 only, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8047164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8047164</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8047164" 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/10.1038/370456a0" target="_blank">Full Text</a>]
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Bond, C. T., Pessia, M., Xia, X.-M., Lagrutta, A., Kavanaugh, M. P., Adelman, J. P.
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<strong>Cloning and expression of a family of inward rectifier potassium channels.</strong>
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Receptors Channels 2: 183-191, 1994. Note: Erratum: Receptors Channels 2: following 350, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874445</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Calloe, K., Ravn, L. S., Schmitt, N., Sui, J. L., Duno, M., Haunso, S., Grunnet, M., Svendsen, J. H., Olesen, S.-P.
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<strong>Characterizations of a loss-of-function mutation in the Kir3.4 channel subunit.</strong>
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Biochem. Biophys. Res. Commun. 364: 889-895, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17967416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17967416</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17967416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2007.10.106" target="_blank">Full Text</a>]
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Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D. A., Hatch, M. M., Hurt, D. E., Lin, L., Xekouki, P., Stratakis, C. A., Chrousos, G. P.
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<strong>A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension.</strong>
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J. Clin. Endocr. Metab. 97: E1532-E1539, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22628607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22628607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22628607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22628607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2012-1334" target="_blank">Full Text</a>]
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Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P.
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<strong>K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.</strong>
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Science 331: 768-772, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21311022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21311022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21311022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21311022" 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.1198785" target="_blank">Full Text</a>]
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Corey, S., Clapham, D. E.
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<strong>Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers.</strong>
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J. Biol. Chem. 273: 27499-27504, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9765280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9765280</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9765280" 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.273.42.27499" target="_blank">Full Text</a>]
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He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., Logothetis, D. E.
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<strong>Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the beta-gamma subunits of G proteins.</strong>
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J. Biol. Chem. 277: 6088-6096, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741896</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741896" 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.M104851200" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Ji1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ji, S., John, S. A., Lu, Y., Weiss, J. N.
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<strong>Mechanosensitivity of the cardiac muscarinic potassium channel: a novel property conferred by Kir3.4 subunit.</strong>
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J. Biol. Chem. 273: 1324-1328, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9430664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9430664</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9430664" 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.273.3.1324" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Kennedy1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kennedy, M. E., Nemec, J., Corey, S., Wickman, K., Clapham, D. E.
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<strong>GIRK4 confers appropriate processing and cell surface localization to G-protein-gated potassium channels.</strong>
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J. Biol. Chem. 274: 2571-2582, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9891030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9891030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9891030" 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.274.4.2571" target="_blank">Full Text</a>]
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<a id="Kokunai2014" class="mim-anchor"></a>
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<div class="">
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Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P.
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<strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong>
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Neurology 82: 1058-1064, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24574546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24574546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24574546" 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/10.1212/WNL.0000000000000239" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Krapivinsky1995" class="mim-anchor"></a>
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<p class="mim-text-font">
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Krapivinsky, G., Gordon, E. A., Wickman, K., Velimirovic, B., Krapivinsky, L., Clapham, D. E.
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<strong>The G-protein-gated atrial K+ channel I-KACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.</strong>
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Nature 374: 135-141, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7877685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7877685</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7877685" 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/10.1038/374135a0" target="_blank">Full Text</a>]
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<a id="Mulatero2012" class="mim-anchor"></a>
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Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others.
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<strong>KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.</strong>
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Hypertension 59: 235-240, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22203740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22203740</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22203740" 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/10.1161/HYPERTENSIONAHA.111.183996" target="_blank">Full Text</a>]
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<a id="Murthy2014" class="mim-anchor"></a>
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Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M.
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<strong>Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.</strong>
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Hypertension 63: 783-789, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24420545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24420545</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24420545" 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/10.1161/HYPERTENSIONAHA.113.02234" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Perry2008" class="mim-anchor"></a>
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Perry, C. A., Pravetoni, M., Teske, J. A., Aguado, C., Erickson, D. J., Medrano, J. F., Lujan, R., Kotz, C. M., Wickman, K.
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<strong>Predisposition to late-onset obesity in GIRK4 knockout mice.</strong>
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Proc. Nat. Acad. Sci. 105: 8148-8153, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18523006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18523006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18523006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18523006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0803261105" target="_blank">Full Text</a>]
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<a id="Scholl2012" class="mim-anchor"></a>
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Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P.
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<strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong>
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Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22308486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22308486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1121407109" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Tucker1995" class="mim-anchor"></a>
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Tucker, S. J., James, M. R., Adelman, J. P.
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<strong>Assignment of K(ATP)-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24.</strong>
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Genomics 28: 127-128, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590741</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7590741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1995.1121" target="_blank">Full Text</a>]
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<a id="Wickman1997" class="mim-anchor"></a>
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Wickman, K., Seldin, M. F., Gendler, S. J., Clapham, D. E.
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<strong>Partial structure, chromosome localization, and expression of the mouse Girk4 gene.</strong>
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Genomics 40: 395-401, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9073506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9073506</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9073506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4599" target="_blank">Full Text</a>]
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<a id="Yang2010" class="mim-anchor"></a>
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Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H. B., Ellinor, P. T., Gao, L., Lin, X., Li, L., and 9 others.
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<strong>Identification of a Kir3.4 mutation in congenital long QT syndrome.</strong>
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Am. J. Hum. Genet. 86: 872-880, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20560207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20560207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20560207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.04.017" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 6/6/2014
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Marla J. F. O'Neill - updated : 6/6/2014<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Ada Hamosh - updated : 5/6/2011<br>Marla J. F. O'Neill - updated : 7/15/2010<br>Cassandra L. Kniffin - updated : 6/30/2009<br>Matthew B. Gross - updated : 7/27/2007<br>Patricia A. Hartz - updated : 5/8/2007<br>Jennifer P. Macke - updated : 11/24/1997
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 8/17/1995
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alopez : 03/21/2023
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carol : 04/25/2017<br>carol : 04/23/2017<br>alopez : 03/16/2015<br>carol : 6/13/2014<br>alopez : 6/12/2014<br>mcolton : 6/6/2014<br>mcolton : 6/6/2014<br>carol : 4/23/2014<br>mcolton : 4/22/2014<br>ckniffin : 4/21/2014<br>terry : 4/4/2013<br>alopez : 5/10/2011<br>terry : 5/6/2011<br>carol : 7/15/2010<br>wwang : 7/27/2009<br>ckniffin : 6/30/2009<br>mgross : 7/27/2007<br>mgross : 7/27/2007<br>terry : 5/8/2007<br>alopez : 12/17/1997<br>alopez : 12/11/1997<br>alopez : 12/11/1997<br>alopez : 12/9/1997<br>terry : 9/11/1995<br>mark : 8/17/1995
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POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5
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CARDIAC INWARD RECTIFIER; CIR<br />
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G PROTEIN-ACTIVATED INWARDLY RECTIFYING POTASSIUM CHANNEL 4; GIRK4<br />
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INWARDLY RECTIFYING POTASSIUM CHANNEL KIR3.4<br />
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KATP1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KCNJ5</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 703234002;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<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: 11q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:128,891,356-128,921,163 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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11q24.3
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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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Hyperaldosteronism, familial, type III
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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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613677
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Long QT syndrome 13
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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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613485
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>G protein-sensitive inwardly rectifying potassium channels, such as KCNJ5, are activated through direct interactions of their cytoplasmic N and C termini with the beta (see GNB1; 139380)-gamma (see GNG2; 606981) subunits of G proteins. KCNJ proteins contain 2 transmembrane domains that surround the P region, which harbors the potassium ion selectivity filter. KCNJ5 can pair with KCNJ3 (601534) to form a highly active heteromultimer, or it can form a low to moderately active homomultimer (He et al., 2002). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ashford et al. (1994) cloned rat Kcnj5 and isolated the human homolog. Tucker et al. (1995) noted that the primary structure of KCNJ5 placed it in the J subfamily of inwardly rectifying potassium channels (Bond et al., 1994), which includes KCNJ2 (600681) and KCNJ4 (600504). </p><p>Wickman et al. (1997) cloned the mouse Girk4 gene and reported a partial sequence of human GIRK4. They showed that Girk4 was expressed almost exclusively in mouse heart. </p><p>Perry et al. (2008) identified prominent Girk4 expression mouse hypothalamus, with most pronounced expression in the ventromedial, paraventricular, and arcuate nuclei, neuron populations implicated in energy homeostasis. </p><p>Using atrial and endocardial left ventricular tissue samples from 4 patients undergoing cardiac valve surgery, Yang et al. (2010) demonstrated by Western blotting that Kir3.4 is expressed in human atria and ventricles. </p><p>Kokunai et al. (2014) found significant expression of the KCNJ5 gene in human skeletal muscle. </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 PCR screening of somatic cell hybrids, radiation hybrids, and YACs, Tucker et al. (1995) mapped the KCNJ5 gene to chromosome 11q24, approximately 500 kb telomeric to the Friend leukemia virus integration site (193067). Using human/rodent somatic cell hybrids, Wickman et al. (1997) localized the human KCNJ5 gene to chromosome 11, consistent with previous studies that localized the gene to 11q23-ter. </p><p>Using interspecific backcross analysis, Wickman et al. (1997) mapped the mouse Girk4 gene to chromosome 9, consistent with the mapping of human GIRK4 to chromosome 11. </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>Ashford et al. (1994) reported that rat Kcnj5 exhibited all the essential features of native cardiac ATP-sensitive potassium (KATP) channels when expressed in various cell lines. However, Krapivinsky et al. (1995) found that rat Kcnj5, which they called Cir, formed a unique potassium channel when expressed in multiple cell lines, but it did not constitute KATP by itself. They demonstrated that coexpression of Kcnj5 with Girk1 (KCNJ3) resulted in a significantly increased G protein-gated inwardly rectifying potassium current that showed properties similar to those of the atrial potassium channel IKACh, which is involved in acetylcholine (ACh)-dependent slowing of the heart rate. Krapivinsky et al. (1995) proposed that atrial IKACh is a heteromultimer composed of GIRK1 and CIR. Subsequently, Ashford et al. (1994) issued a retraction stating that they could not replicate their findings suggesting that Kcnj5 encodes a subunit of cardiac KATP channels. </p><p>Corey and Clapham (1998) found that only about half of the Girk4 purified from bovine atria was associated with Girk1 in a heterotetramer, whereas the remaining Girk4 formed a high molecular mass, SDS-resistant complex lacking Girk1. They noted that recombinant Girk4 homomultimers had been shown to produce large whole cell currents with long single channel open times (Ji et al., 1998). </p><p>Using an extracellular epitope tag on rat Girk1, Kennedy et al. (1999) demonstrated that Girk1 required association with Girk4 for cell surface localization. Girk4 associated with Girk1 during or shortly after subunit synthesis and allowed appropriate glycosylation of the Girk1 subunit to a form seen in native atrial tissue. The C terminus of Girk4 was required for cell surface localization. Girk1 appeared intracellular in atrial myocytes isolated from Girk4-knockout mice, and it was not maturely glycosylated, supporting an essential role for GIRK4 in processing and cell surface localization of GIRK1/GIRK4 channels in vivo. </p><p>Using biochemical and electrophysiologic approaches, He et al. (2002) found that his64 and leu268 mediated human GIRK4 activity and that mutation of these sites significantly reduced binding of GIRK4 to G-beta-gamma dimers. In GIRK4/GIRK1 heterodimers, his64 and leu268 in GIRK4 contributed more to G protein sensitivity than did the corresponding his57 and leu262 residues of GIRK1. Mutation of these residues in GIRK4 or GIRK1 abolished all G protein-mediated currents. He et al. (2002) stated that mutation of leu339 in GIRK4 or leu333 in GIRK1 abolished agonist-induced G protein-mediated currents, but not agonist-independent G protein-mediated currents. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Long QT Syndrome</em></strong></p><p>
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In a large 4-generation Chinese family with autosomal dominant long QT syndrome mapping to chromosome 11q23.3-q23.4 (LQT13; 613485), Yang et al. (2010) sequenced the candidate gene KCNJ5 and identified heterozygosity for a missense mutation (G387R; 600734.0001) in affected individuals. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies demonstrated that the mutation has a dominant-negative effect that results in near-complete loss of channel activity compared to wildtype. </p><p><strong><em>Familial Hyperaldosteronism Type III</em></strong></p><p>
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Choi et al. (2011) identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5 present in 8 of 22 human aldosterone-producing adrenal adenomas: G151R (600734.0004) and L168R. In addition, Choi et al. (2011) identified heterozygosity for a missense mutation in KCNJ5 (T158A; 600734.0002) in a family segregating autosomal dominant hyperaldosteronism type III (HALD3; 613677). This mutation caused increased sodium conductance and severe aldosteronism and massive bilateral adrenal hyperplasia. </p><p>In an Italian mother and daughter with primary aldosteronism, Mulatero et al. (2012) identified heterozygosity for a missense mutation in the KCNJ5 gene (G151E; 600734.0005). </p><p>In a mother and daughter with severe aldosteronism requiring total adrenalectomy, Charmandari et al. (2012) identified heterozygosity for a missense mutation in the KCNJ5 gene (I157S; 600734.0006). </p><p>Murthy et al. (2014) analyzed the KCNJ5 gene in 251 patients with apparent sporadic florid primary aldosteronism, and identified 3 heterozygous missense mutations, G247R (rs200170681; 600734.0003), E246K (600734.0007), and R52H (rs144062083). In addition, 12 (5%) of the 251 patients carried the rare SNP E282Q (rs7102584), present in a population frequency of 2% in the 1000 Genomes cohort. Although remote from the KCNJ5 selectivity filter, 3 of the 4 variants (E246K, R52H, and E282Q) were shown to alter inward rectification, conduction of Na+ currents, and angiotensin II (106150)-induced aldosterone release in the H295R cell line, a well-established model for the human zona glomerulosa cell. Results of electrophysiologic analysis of the G247R channel, however, were indistinguishable from those of the wildtype channel. </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>Genotype/Phenotype Correlations</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 affected members of 4 unrelated families with early-onset primary hyperaldosteronism, Scholl et al. (2012) identified heterozygosity for missense mutations in the KCNJ5 gene: G151R in 2 families with severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control, and G151E in 2 families that had more easily controlled hypertension and no evidence of adrenal hyperplasia. Electrophysiologic analysis demonstrated that although both mutations alter the K+ selectivity of the channel, the G151E mutation causes much greater Na+ conductance than G151R, resulting in rapid Na(+)-dependent cell lethality. Scholl et al. (2012) proposed that the increased lethality associated with the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus paradoxically resulting in a milder phenotype in those patients. </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>Perry et al. (2008) showed that Girk4-null mice were predisposed to late-onset obesity (601665). By 9 months, Girk4-null mice were approximately 25% heavier than wildtype controls due to greater body fat. Before the development of overweight, Girk4-null mice exhibited a tendency toward greater food intake and an increased propensity to work for food in an operant task. Girk4-null mice also exhibited reduced net energy expenditure, despite displaying elevated resting heart rates and core body temperatures. These data implicated GIRK4-containing channels in signaling crucial to energy homeostasis and body weight. </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>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 LONG QT SYNDROME 13</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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KCNJ5, GLY387ARG
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<br />
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SNP: rs199830292,
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gnomAD: rs199830292,
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ClinVar: RCV000009405, RCV000193019, RCV000312115, RCV000865749, RCV003162221
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large 4-generation Chinese family with autosomal dominant long QT syndrome (LQT13; 613485), Yang et al. (2010) identified heterozygosity for a 1473C-G transversion in the KCNJ5 gene, resulting in a gly387-to-arg (G387R) substitution at a highly conserved residue. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies in HEK293 cells cotransfected with Kir3.4 and Kir3.1 (KCNJ3; 601534) demonstrated that the mutant has a dominant-negative effect resulting in drastic reduction of inward currents compared to wildtype. In addition, plasma membrane and intracellular expression levels of Kir3.4 and Kir3.1 were markedly reduced in HEK293 cells cotransfected with the mutation compared to wildtype. </p><p>Kokunai et al. (2014) identified a heterozygous G387R mutation in a 35-year-old Japanese man who developed periodic muscle paralysis associated with reduced serum potassium concentrations beginning at age 31 years. He had no cardiac symptoms, but ECG showed possible sinus arrest during the attacks and prominent U waves at normal potassium concentrations. Although Kokunai et al. (2014) suggested that the phenotype resembled Andersen-Tawil syndrome (170390), the patient did not have dysmorphic features. There was a strong family history of significant cardiac arrhythmia, but neither detailed clinical features nor DNA from family members was available. The patient did not have increased serum aldosterone. The mutation, which was found by exome capture resequencing analysis of 162 genes encoding ion channels and confirmed by Sanger sequencing, was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. In vitro functional expression studies in Xenopus oocytes showed that coexpression of KCNJ2 (600681) with mutant KCNJ5 significantly reduced the inwardly rectifying potassium current compared to that observed with coexpression of KCNJ2 with wildtype KCNJ5. Kokunai et al. (2014) concluded that the reduction in this current caused by loss of function of KCNJ2 is the underlying cause of periodic paralysis and cardiac conduction abnormalities in this patient. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HYPERALDOSTERONISM, FAMILIAL, TYPE III</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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ALDOSTERONE-PRODUCING ADRENAL ADENOMA, SOMATIC, INCLUDED
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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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KCNJ5, THR158ALA
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<br />
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SNP: rs387906778,
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ClinVar: RCV000023035, RCV000122747, RCV000194572
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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 />
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<p><strong><em>Familial Hyperaldosteronism Type III</em></strong></p><p>
|
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In a father and 2 daughters with hyperaldosteronism type III (HALD3; 613677), Choi et al. (2011) identified heterozygosity for an A-to-G transition in the KCNJ5 gene resulting in a threonine-to-alanine substitution at codon 158 (T158A). This mutation was present in affected family members and was not identified in 900 control alleles. All 3 patients had massive adrenal hyperplasia and required bilateral adrenalectomy in childhood. Threonine-158 is conserved among KCNJ5 orthologs and other inward rectifiers and lies in the loop between the selectivity filter and the second transmembrane domain. The T158A mutation eliminates hydrogen bonds that constrain the structure of the KCNJ5 potassium channel. </p><p>Kokunai et al. (2014) identified a T158A mutation in a patient with prolonged QU on ECG recorded at normal potassium concentration who developed a hypokalemic paralytic attack and primary aldosteronism 2 years later. The patient was 1 of 21 Japanese patients with a phenotype resembling Andersen-Tawil syndrome (170390) who did not carry a mutation in the KCNJ2 gene (600681). </p><p><strong><em>Aldosterone-Producing Adrenal Adenoma</em></strong></p><p>
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In an aldosterone-producing adrenal adenoma from an Italian patient with primary aldosteronism, Mulatero et al. (2012) identified a somatic c.472A-G transition, resulting in a thr158-to-ala (T158A) mutation in the KCNJ5 gene. The mutation was not present in germline DNA from peripheral blood. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0003 VARIANT OF UNKNOWN SIGNIFICANCE</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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KCNJ5, GLY247ARG ({dbSNP rs200170681})
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<br />
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SNP: rs200170681,
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gnomAD: rs200170681,
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ClinVar: RCV000122748, RCV001084390, RCV002381433
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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>This variant is classified as a variant of unknown significance because its contribution to atrial fibrillation or hyperaldosteronism has not been confirmed.</p><p>Calloe et al. (2007) analyzed the candidate gene KCNJ5 in 158 patients with documented atrial fibrillation (AF; see 608583) followed by restored sinus rhythm, and identified a 69-year-old woman who had a single episode of AF that spontaneously reverted after 3 days; she was heterozygous for a 739G-A transition, resulting in a gly247-to-arg (G247R) substitution at a highly conserved residue in the cytoplasmic region of the Kir3.4 C terminus. The mutation was also detected in heterozygosity in her unaffected 48-year-old son, but was not found in her 4 other sons, in 96 controls, or in the PharmGKB or NCBI SNP databases. The patient was negative for mutation in 8 other known AF-associated genes. Functional analysis in Xenopus oocytes showed reduction of basal current with the G247R mutant compared to wildtype, and coexpression with the muscarinic acetylcholine receptor type 2 (CHRM2; 118493) showed a severe decrease in acetylcholine-induced current, indicating that the G247R mutant interferes with activation by the stimulatory G-beta-gamma subunits. Coexpression with wildtype Kir3.4 or Kir3.1 (KCNJ3; 601534) channels had a compensating effect on both basal current levels and the response to muscarinic stimulation, suggesting that function of Kir3.4-G247R is compensated in vivo, which Calloe et al. (2007) proposed might explain the lack of clear clinical manifestations. </p><p>Murthy et al. (2014) identified the G247R mutation in a woman who was diagnosed at 38 years of age with florid primary aldosteronism (see 613677). However, electrophysiologic studies in Xenopus oocytes showed that a high-Na+ bath solution did not alter the resting potential of the G247R channel, and permeability of the mutant channel was similar to wildtype in high-K+ or high-Na+ bath solutions, exhibiting typical inward rectification in the former and almost no measurable current in the latter. Functional analysis in transiently transfected H295R cells demonstrated that G247R behaved indistinguishably from wildtype, showing no change in basal or angiotensin II (106150)-induced aldosterone release. Murthy et al. (2014) concluded that the patient's aldosteronism had another cause. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 ALDOSTERONE-PRODUCING ADRENAL ADENOMA, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HYPERALDOSTERONISM, FAMILIAL, TYPE III, INCLUDED
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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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KCNJ5, GLY151ARG
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<br />
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SNP: rs386352319,
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ClinVar: RCV000122472, RCV000122749, RCV000122750, RCV002326795, RCV003531964
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</span>
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</div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Aldosterone-Producing Adrenal Adenoma</em></strong></p><p>
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In 2 of 22 aldosterone-producing adrenal adenomas (APAs) from unrelated patients with primary hyperaldosteronism (613677), Choi et al. (2011) identified a somatic G-to-A transition at position chr11:126,286,829 in the KCNJ5 gene, resulting in a gly151-to-arg (G151R) substitution. </p><p>In an APA from a patient from Wurzburg with primary hyperaldosteronism, Mulatero et al. (2012) identified a somatic KCNJ5 G151R mutation. The mutation was not present in germline DNA from peripheral blood. </p><p><strong><em>Familial Hyperaldosteronism Type III</em></strong></p><p>
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In affected individuals from 2 unrelated families with early-onset hyperaldosteronism (HALD3; 613677), Scholl et al. (2012) identified heterozygosity for a 451G-A transition in the KCNJ5 gene, resulting in the G151R substitution. The mutation was not found in unaffected family members or in 6,000 control chromosomes. Patients carrying the G151R mutation had severe, spironolactone-unresponsive aldosteronism that worsened with age and required bilateral adrenalectomy. Scholl et al. (2012) stated that somatic G151R mutations had previously been detected in 86 aldosterone-producing adenomas (23% of all APAs). Electrophysiologic analysis in transfected mammalian 293T cells demonstrated that the G151R mutation results in increased Na+ conductance, although to a lesser extent than G151E (600743.0005). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 HYPERALDOSTERONISM, FAMILIAL, TYPE III</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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KCNJ5, GLY151GLU
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<br />
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SNP: rs587777437,
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gnomAD: rs587777437,
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ClinVar: RCV000122751, RCV001210015
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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 an Italian mother and daughter with primary hyperaldosteronism (HALD3; 613677), Mulatero et al. (2012) identified heterozygosity for a c.452G-A transition in the KCNJ5 gene, resulting in a gly151-to-glu (G151E) substitution at a conserved residue in the selectivity filter. Electrophysiologic analysis in transfected HEK cells revealed that the mutant channel is no longer K+ selective but is similarly permeable to Na+ and K+. Both patients had normal-appearing adrenal glands by CT scan, and their symptoms were controlled by medication. </p><p>In affected individuals from 2 unrelated families with early-onset hyperaldosteronism, Scholl et al. (2012) identified heterozygosity for the G151E substitution in the KCNJ5 gene. The mutation was not found in unaffected family members or in 6,000 control chromosomes. Patients carrying the G151E mutation had remarkable responsiveness to spironolactone and did not require adrenalectomy; in 1 G151E carrier who underwent adrenalectomy before availability of spironolactone, adrenal histology was reported as normal. Scholl et al. (2012) noted that in contrast to the G151R mutation (600734.0004), G151E had not been observed in adrenal adenomas, suggesting that G151E cannot support development of increased adrenal cell mass. Electrophysiologic analysis in transfected mammalian 293T cells demonstrated that the G151E mutation results in much greater Na+ conductance than G151R, leading to rapid Na(+)-dependent cell lethality. Scholl et al. (2012) suggested that the increased lethality of the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus resulting in a milder phenotype in those patients. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 HYPERALDOSTERONISM, FAMILIAL, TYPE III</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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KCNJ5, ILE157SER
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<br />
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SNP: rs587777438,
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ClinVar: RCV000122752
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a mother and daughter with severe hyperaldosteronism (HALD3; 613677) requiring total adrenalectomy, Charmandari et al. (2012) identified heterozygosity for a 470G-T transversion in the KCNJ5 gene, resulting in an ile157-to-ser (I157S) substitution at a highly conserved residue at the C-terminal end of the loop leading away from the selectivity filter. Whole-cell voltage clamp recordings in HEK293T cells coexpressing Kir3.4 and Kir3.1 (KCNJ3; 601534) channels demonstrated loss of channel selectivity and less negative reversal potentials with I157S mutant Kir3.4 compared to wildtype. Charmandari et al. (2012) concluded that mutations near the channel pore result in loss of K+ selectivity and increased Na+ conductance, resulting in increased cell membrane depolarization, increased Ca2+ entry into adrenal glomerulosa cells, and increased aldosterone synthesis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 HYPERALDOSTERONISM, FAMILIAL, TYPE III</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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KCNJ5, GLU246LYS
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<br />
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SNP: rs587777439,
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gnomAD: rs587777439,
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ClinVar: RCV000122753
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman who was diagnosed at 37 years of age with primary hyperaldosteronism (HALD3; 613677) and who had bilateral adrenal hyperplasia diagnosed by CT scan and adrenal vein sampling, Murthy et al. (2014) identified heterozygosity for a c.736G-A transition in the KCNJ5 gene, resulting in a glu246-to-lys (E246K) substitution at a highly conserved residue. Electrophysiologic studies in Xenopus oocytes showed significant depolarization of the E246K channel in a high-Na+ bath solution, with no clear rectification of the mutant channel in a high-K+ bath solution; switching from a high-K+ to a high-Na+ bath solution showed virtually no change in the I-V curve, confirming a substantial loss of K+ selectivity in the mutant channel. Functional analysis in transiently transfected H295R cells demonstrated a 2- to 3-fold increase in angiotensin II (106150)-induced aldosterone release with the E246K mutant compared to wildtype. In addition, H295R cells transfected with the E246K mutant showed significantly reduced viability after 48 hours of culture. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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|
</span>
|
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Ashford, M. L. J., Bond, C. T., Blair, T. A., Adelman, J. P.
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<strong>Cloning and functional expression of a rat heart KATP channel.</strong>
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|
Nature 370: 456-459, 1994. Note: Retraction: Nature 378: 792 only, 1995.
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[PubMed: 8047164]
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[Full Text: https://doi.org/10.1038/370456a0]
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<li>
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<p class="mim-text-font">
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Bond, C. T., Pessia, M., Xia, X.-M., Lagrutta, A., Kavanaugh, M. P., Adelman, J. P.
|
|
<strong>Cloning and expression of a family of inward rectifier potassium channels.</strong>
|
|
Receptors Channels 2: 183-191, 1994. Note: Erratum: Receptors Channels 2: following 350, 1994.
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[PubMed: 7874445]
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<li>
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<p class="mim-text-font">
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Calloe, K., Ravn, L. S., Schmitt, N., Sui, J. L., Duno, M., Haunso, S., Grunnet, M., Svendsen, J. H., Olesen, S.-P.
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<strong>Characterizations of a loss-of-function mutation in the Kir3.4 channel subunit.</strong>
|
|
Biochem. Biophys. Res. Commun. 364: 889-895, 2007.
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[PubMed: 17967416]
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[Full Text: https://doi.org/10.1016/j.bbrc.2007.10.106]
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<li>
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<p class="mim-text-font">
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Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D. A., Hatch, M. M., Hurt, D. E., Lin, L., Xekouki, P., Stratakis, C. A., Chrousos, G. P.
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<strong>A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension.</strong>
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J. Clin. Endocr. Metab. 97: E1532-E1539, 2012.
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[PubMed: 22628607]
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[Full Text: https://doi.org/10.1210/jc.2012-1334]
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<p class="mim-text-font">
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Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P.
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<strong>K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.</strong>
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Science 331: 768-772, 2011.
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[PubMed: 21311022]
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[Full Text: https://doi.org/10.1126/science.1198785]
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<li>
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<p class="mim-text-font">
|
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Corey, S., Clapham, D. E.
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<strong>Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers.</strong>
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J. Biol. Chem. 273: 27499-27504, 1998.
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[PubMed: 9765280]
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[Full Text: https://doi.org/10.1074/jbc.273.42.27499]
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He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., Logothetis, D. E.
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<strong>Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the beta-gamma subunits of G proteins.</strong>
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J. Biol. Chem. 277: 6088-6096, 2002.
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[PubMed: 11741896]
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[Full Text: https://doi.org/10.1074/jbc.M104851200]
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<p class="mim-text-font">
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Ji, S., John, S. A., Lu, Y., Weiss, J. N.
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<strong>Mechanosensitivity of the cardiac muscarinic potassium channel: a novel property conferred by Kir3.4 subunit.</strong>
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J. Biol. Chem. 273: 1324-1328, 1998.
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[PubMed: 9430664]
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[Full Text: https://doi.org/10.1074/jbc.273.3.1324]
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<p class="mim-text-font">
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Kennedy, M. E., Nemec, J., Corey, S., Wickman, K., Clapham, D. E.
|
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<strong>GIRK4 confers appropriate processing and cell surface localization to G-protein-gated potassium channels.</strong>
|
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J. Biol. Chem. 274: 2571-2582, 1999.
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[PubMed: 9891030]
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[Full Text: https://doi.org/10.1074/jbc.274.4.2571]
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<li>
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<p class="mim-text-font">
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Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., Takahashi, M. P.
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<strong>A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.</strong>
|
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Neurology 82: 1058-1064, 2014.
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[PubMed: 24574546]
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[Full Text: https://doi.org/10.1212/WNL.0000000000000239]
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<p class="mim-text-font">
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Krapivinsky, G., Gordon, E. A., Wickman, K., Velimirovic, B., Krapivinsky, L., Clapham, D. E.
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<strong>The G-protein-gated atrial K+ channel I-KACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.</strong>
|
|
Nature 374: 135-141, 1995.
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[PubMed: 7877685]
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[Full Text: https://doi.org/10.1038/374135a0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others.
|
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<strong>KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.</strong>
|
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Hypertension 59: 235-240, 2012.
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[PubMed: 22203740]
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[Full Text: https://doi.org/10.1161/HYPERTENSIONAHA.111.183996]
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</p>
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<li>
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<p class="mim-text-font">
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|
Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M.
|
|
<strong>Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.</strong>
|
|
Hypertension 63: 783-789, 2014.
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[PubMed: 24420545]
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[Full Text: https://doi.org/10.1161/HYPERTENSIONAHA.113.02234]
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<li>
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<p class="mim-text-font">
|
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Perry, C. A., Pravetoni, M., Teske, J. A., Aguado, C., Erickson, D. J., Medrano, J. F., Lujan, R., Kotz, C. M., Wickman, K.
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<strong>Predisposition to late-onset obesity in GIRK4 knockout mice.</strong>
|
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Proc. Nat. Acad. Sci. 105: 8148-8153, 2008.
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[PubMed: 18523006]
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[Full Text: https://doi.org/10.1073/pnas.0803261105]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P.
|
|
<strong>Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.</strong>
|
|
Proc. Nat. Acad. Sci. 109: 2533-2538, 2012.
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|
[PubMed: 22308486]
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[Full Text: https://doi.org/10.1073/pnas.1121407109]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Tucker, S. J., James, M. R., Adelman, J. P.
|
|
<strong>Assignment of K(ATP)-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24.</strong>
|
|
Genomics 28: 127-128, 1995.
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|
[PubMed: 7590741]
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[Full Text: https://doi.org/10.1006/geno.1995.1121]
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Wickman, K., Seldin, M. F., Gendler, S. J., Clapham, D. E.
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<strong>Partial structure, chromosome localization, and expression of the mouse Girk4 gene.</strong>
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Genomics 40: 395-401, 1997.
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[PubMed: 9073506]
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[Full Text: https://doi.org/10.1006/geno.1997.4599]
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Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H. B., Ellinor, P. T., Gao, L., Lin, X., Li, L., and 9 others.
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<strong>Identification of a Kir3.4 mutation in congenital long QT syndrome.</strong>
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Am. J. Hum. Genet. 86: 872-880, 2010.
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[PubMed: 20560207]
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[Full Text: https://doi.org/10.1016/j.ajhg.2010.04.017]
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Marla J. F. O'Neill - updated : 6/6/2014<br>Marla J. F. O'Neill - updated : 6/6/2014<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Ada Hamosh - updated : 5/6/2011<br>Marla J. F. O'Neill - updated : 7/15/2010<br>Cassandra L. Kniffin - updated : 6/30/2009<br>Matthew B. Gross - updated : 7/27/2007<br>Patricia A. Hartz - updated : 5/8/2007<br>Jennifer P. Macke - updated : 11/24/1997
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Victor A. McKusick : 8/17/1995
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alopez : 03/21/2023<br>carol : 04/25/2017<br>carol : 04/23/2017<br>alopez : 03/16/2015<br>carol : 6/13/2014<br>alopez : 6/12/2014<br>mcolton : 6/6/2014<br>mcolton : 6/6/2014<br>carol : 4/23/2014<br>mcolton : 4/22/2014<br>ckniffin : 4/21/2014<br>terry : 4/4/2013<br>alopez : 5/10/2011<br>terry : 5/6/2011<br>carol : 7/15/2010<br>wwang : 7/27/2009<br>ckniffin : 6/30/2009<br>mgross : 7/27/2007<br>mgross : 7/27/2007<br>terry : 5/8/2007<br>alopez : 12/17/1997<br>alopez : 12/11/1997<br>alopez : 12/11/1997<br>alopez : 12/9/1997<br>terry : 9/11/1995<br>mark : 8/17/1995
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