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Entry
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- *600681 - POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 2; KCNJ2
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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">*600681</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</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/600681">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000123700;t=ENST00000243457" 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=3759" 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=600681" 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=ENSG00000123700;t=ENST00000243457" 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_000891" 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_000891" 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=600681" 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=02815&isoform_id=02815_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/KCNJ2" 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/595931,625092,727363,833706,2282068,2460308,4504835,8132297,8132301,54037433,77157479,119609498,189054259" 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/P63252" 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=3759" 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=ENSG00000123700;t=ENST00000243457" 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=KCNJ2" 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=KCNJ2" 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+3759" 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/KCNJ2" 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:3759" 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/3759" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr17&hgg_gene=ENST00000243457.4&hgg_start=70169532&hgg_end=70180044&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:6263" 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/kcnj2" 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=600681[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=600681[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/KCNJ2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000123700" 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=KCNJ2" 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=KCNJ2" 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=KCNJ2" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=KCNJ2" title="Zhejiang University-Adinovo Center KCNJ2 Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University-Adinov…</a></div><div style="margin-left: 0.5em;"><a href="http://www.fsm.it/cardmoc/" title="Gene Connection for the Heart" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Gene Connection for the He…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KCNJ2&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/PA214" 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:6263" 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:104744" 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/KCNJ2#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:104744" 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/3759/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=3759" 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-091204-290" 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:3759" 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=KCNJ2&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> 422348008<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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600681
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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 2; KCNJ2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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HHIRK1<br />
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IRK1<br />
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KIR2.1
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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=KCNJ2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KCNJ2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/17/893?start=-3&limit=10&highlight=893">17q24.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:70169532-70180044&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">17:70,169,532-70,180,044</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=170390,613980,609622" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
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="3">
|
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<span class="mim-font">
|
|
<a href="/geneMap/17/893?start=-3&limit=10&highlight=893">
|
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17q24.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Andersen syndrome
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/170390"> 170390 </a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<p>The KCNJ2 gene encodes the strong inward rectifier K+ channel protein Kir2.1 (summary by <a href="#6" class="mim-tip-reference" title="Deo, M., Ruan, Y., Pandit, S. V., Shah, K., Berenfeld, O., Blaufox, A., Cerrone, M., Noujaim, S. F., Denegri, M., Jalife, J., Priori, S. G. <strong>KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.</strong> Proc. Nat. Acad. Sci. 110: 4291-4296, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23440193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23440193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23440193[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.1218154110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23440193">Deo et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23440193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Raab-Graham, K., Radeke, C. M., Vandenberg, C. A. <strong>Molecular cloning and expression of a human heart inward rectifier potassium channel.</strong> Neuroreport 5: 2501-2505, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7696590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7696590</a>] [<a href="https://doi.org/10.1097/00001756-199412000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7696590">Raab-Graham et al. (1994)</a> used low stringency colony hybridization with the complete coding region of the mouse IRK gene (<a href="#12" class="mim-tip-reference" title="Kubo, Y., Baldwin, T. J., Jan, Y. N., Jan, L. Y. <strong>Primary structure and functional expression of a mouse inward rectifier potassium channel.</strong> Nature 362: 127-133, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7680768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7680768</a>] [<a href="https://doi.org/10.1038/362127a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7680768">Kubo et al., 1993</a>) to isolate cDNA from human heart that encodes an inwardly rectifying potassium channel, KCNJ2. <a href="#22" class="mim-tip-reference" title="Raab-Graham, K., Radeke, C. M., Vandenberg, C. A. <strong>Molecular cloning and expression of a human heart inward rectifier potassium channel.</strong> Neuroreport 5: 2501-2505, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7696590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7696590</a>] [<a href="https://doi.org/10.1097/00001756-199412000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7696590">Raab-Graham et al. (1994)</a> symbolized the gene HHIRK1. The cDNA encodes a 427-amino acid protein with 2 putative transmembrane domains and an H5 region. Expression of HHIRK1 in Xenopus oocytes demonstrated strong inward rectification that was blocked by both extracellular barium and cesium ions, and they measured a single channel conductance of 30 pS. Northern blot analysis demonstrated a single 5.5-kb transcript with high levels in heart, brain, placenta, lung, and skeletal muscle. Lower levels were present in kidney. The HHIRK1 message was found in all brain subregions tested, particularly in the caudate nucleus, corpus callosum, and substantia nigra. In regions of sequence overlap, HHIRK1 shares 66 to 67% identity with a small conductance human potassium channel (KCNJ4; <a href="/entry/600504">600504</a>). Because of similarities in channel properties, <a href="#22" class="mim-tip-reference" title="Raab-Graham, K., Radeke, C. M., Vandenberg, C. A. <strong>Molecular cloning and expression of a human heart inward rectifier potassium channel.</strong> Neuroreport 5: 2501-2505, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7696590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7696590</a>] [<a href="https://doi.org/10.1097/00001756-199412000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7696590">Raab-Graham et al. (1994)</a> suggested that HHIRK1 was the prominent cardiac inward rectifier. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7680768+7696590" 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="#7" class="mim-tip-reference" title="Derst, C., Karschin, C., Wischmeyer, E., Hirsch, J. R., Preisig-Muller, R., Rajan, S., Engel, H., Grzeschik, K.-H., Daut, J., Karschin, A. <strong>Genetic and functional linkage of Kir5.1 and Kir2.1 channel subunits.</strong> FEBS Lett. 491: 305-311, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11240146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11240146</a>] [<a href="https://doi.org/10.1016/s0014-5793(01)02202-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11240146">Derst et al. (2001)</a> determined that the KCNJ2 gene contains 2 exons and spans approximately 10 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11240146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Raab-Graham, K., Radeke, C. M., Vandenberg, C. A. <strong>Molecular cloning and expression of a human heart inward rectifier potassium channel.</strong> Neuroreport 5: 2501-2505, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7696590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7696590</a>] [<a href="https://doi.org/10.1097/00001756-199412000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7696590">Raab-Graham et al. (1994)</a> mapped the HHIRK1 gene to human chromosome 17 by PCR amplification from a somatic cell hybrid panel. This location is consistent with the mapping of mouse IRK1 to a distal region of mouse chromosome 11 that shares homology with human chromosome 17. (See also KCNJ1, <a href="/entry/600359">600359</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7696590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By radiation hybrid analysis, electronic PCR, and sequence similarity to mapped BACs, <a href="#7" class="mim-tip-reference" title="Derst, C., Karschin, C., Wischmeyer, E., Hirsch, J. R., Preisig-Muller, R., Rajan, S., Engel, H., Grzeschik, K.-H., Daut, J., Karschin, A. <strong>Genetic and functional linkage of Kir5.1 and Kir2.1 channel subunits.</strong> FEBS Lett. 491: 305-311, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11240146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11240146</a>] [<a href="https://doi.org/10.1016/s0014-5793(01)02202-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11240146">Derst et al. (2001)</a> mapped the KCNJ2 gene to chromosome 17q23.1-q24.2, separated by 34 kb from KCNJ16 (<a href="/entry/605722">605722</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11240146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Doyle, D. A., Morais Cabral, J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L., Chait, B. T., MacKinnon, R. <strong>The structure of the potassium channel: molecular basis of K+ conduction and selectivity.</strong> Science 280: 69-77, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9525859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9525859</a>] [<a href="https://doi.org/10.1126/science.280.5360.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9525859">Doyle et al. (1998)</a> determined the atomic structure of a bacterial potassium channel pore by means of x-ray crystallography. However, serious doubts were raised concerning whether the prokaryotic potassium channel pore actually represents those of eukaryotes. <a href="#15" class="mim-tip-reference" title="Lu, Z., Klem, A. M., Ramu, Y. <strong>Ion conduction pore is conserved among potassium channels.</strong> Nature 413: 809-813, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11677598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11677598</a>] [<a href="https://doi.org/10.1038/35101535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11677598">Lu et al. (2001)</a> addressed this issue by substituting the prokaryotic potassium channel pore into eukaryotic voltage-gated (see <a href="/entry/176260">176260</a>) and inward-rectifier potassium channels. The resulting chimeras retained the respective functional hallmarks of the eukaryotic channels, which indicates that the ion conduction pore is indeed conserved among potassium channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9525859+11677598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Preisig-Muller, R., Schlichthorl, G., Goerge, T., Heinen, S., Bruggemann, A., Rajan, S., Derst, C., Veh, R. W., Daut, J. <strong>Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome.</strong> Proc. Nat. Acad. Sci. 99: 7774-7779, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12032359[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.102609499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12032359">Preisig-Muller et al. (2002)</a> demonstrated that heteromerization of Kir2.1 channels with wildtype Kir2.2 and Kir2.3 channels contributes to the phenotype of Andersen syndrome (<a href="/entry/170390">170390</a>). Coexpression of Kir2.1 mutants related to Andersen syndrome with wildtype Kir2.x channels showed a dominant negative effect, the extent of which varied between different mutants. The results suggested that differential tetramerization of the mutant allele of Kir2.1 with wildtype Kir2.1, Kir2.2, and Kir2.3 channels represents the molecular basis of the extraordinary pleiotropy and variability of Andersen syndrome. In addition to cardiac arrhythmias and periodic paralysis, dysmorphic features include scoliosis, low-set ears, wide-set eyes, small chin, and broad forehead, but expression of these traits is highly variable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12032359" 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="Miake, J., Marban, E., Nuss, H. B. <strong>Biological pacemaker created by gene transfer.</strong> Nature 419: 132-133, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12226654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12226654</a>] [<a href="https://doi.org/10.1038/419132b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12226654">Miake et al. (2002)</a> replaced 3 amino acid residues in the pore structure of Kir2.1 with alanine to create a dominant-negative construct that suppresses current when expressed with wildtype Kir2.1. When this construct was packaged with green fluorescent protein (GFP) into a bicistronic adenoviral vector and injected into the left ventricular cavity of guinea pigs during transient cross-clamping of the great vessels, transduction was successful in about 20% of ventricular myocytes, as determined by GFP fluorescence. This suppression of Kir2.1 converted quiescent heart muscle cells into pacemaker cells that successfully generated a spontaneous rhythmic electrical activity in the ventricle in vivo. <a href="#17" class="mim-tip-reference" title="Miake, J., Marban, E., Nuss, H. B. <strong>Biological pacemaker created by gene transfer.</strong> Nature 419: 132-133, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12226654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12226654</a>] [<a href="https://doi.org/10.1038/419132b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12226654">Miake et al. (2002)</a> concluded that genetically engineered pacemakers could be developed as a possible alternative to implantable electronic devices. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12226654" 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>Inwardly rectifying potassium (Kir) channels are important regulators of resting membrane potential and cell excitability. The activity of Kir channels is critically dependent on the integrity of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). Using targeted mutations in KCNJ2 and KCNJ1 (<a href="/entry/600359">600359</a>), which the authors called Kir2.1 and Kir1.1, <a href="#13" class="mim-tip-reference" title="Lopes, C. M. B., Zhang, H., Rohacs, T., Jin, T., Yang, J., Logothetis, D. E. <strong>Alterations in conserved Kir channel-PIP(2) interactions underlie channelopathies.</strong> Neuron 34: 933-944, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12086641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12086641</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00725-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12086641">Lopes et al. (2002)</a> identified residues important for PIP2 interaction. Mutations in residues associated with Andersen syndrome (<a href="/entry/170390">170390</a>) and Bartter syndrome (<a href="/entry/241200">241200</a>) decreased the strength of channel-PIP2 interactions. <a href="#13" class="mim-tip-reference" title="Lopes, C. M. B., Zhang, H., Rohacs, T., Jin, T., Yang, J., Logothetis, D. E. <strong>Alterations in conserved Kir channel-PIP(2) interactions underlie channelopathies.</strong> Neuron 34: 933-944, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12086641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12086641</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00725-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12086641">Lopes et al. (2002)</a> concluded that a decrease in channel-PIP2 interactions underlies the molecular mechanism of Andersen and Bartter syndromes when these mutations are present in patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12086641" 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>To gain insight into the mechanism of arrhythmia susceptibility, <a href="#24" class="mim-tip-reference" title="Tristani-Firouzi, M., Jensen, J. L., Donaldson, M. R., Sansone, V., Meola, G., Hahn, A., Bendahhou, S., Kwiecinski, H., Fidzianska, A., Plaster, N., Fu, Y.-H., Ptacek, L. J., Tawil, R. <strong>Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).</strong> J. Clin. Invest. 110: 381-388, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12163457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163457">Tristani-Firouzi et al. (2002)</a> used a ventricular myocyte model to simulate the effects of reduced Kir2.1. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular potassium ion, induced delayed afterdepolarizations and spontaneous arrhythmias. These findings suggested that the substrate for arrhythmia susceptibility in Andersen syndrome is distinct from that in the other forms of inherited long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163457" 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>Although chloroquine is an important therapeutic agent for treatment of malaria, its safety margin is narrow. Chloroquine inhibits the cardiac inward rectifier K+ current and can induce lethal ventricular arrhythmias. <a href="#23" class="mim-tip-reference" title="Rodriguez-Menchaca, A. A., Navarro-Polanco, R. A., Ferrer-Villada, T., Rupp, J., Sachse, F. B., Tristani-Firouzi, M., Sanchez-Chapula, J. A. <strong>The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel.</strong> Proc. Nat. Acad. Sci. 105: 1364-1368, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18216262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18216262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18216262[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.0708153105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18216262">Rodriguez-Menchaca et al. (2008)</a> found that chloroquine blocked mouse Kir2.1 channels from the cytoplasmic surface in a voltage- and K(+)-dependent manner. Mutagenesis and molecular modeling showed that chloroquine did not penetrate deeply into the channel and was stabilized within the binding pocket by negatively charged and aromatic amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18216262" 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="Epshtein, Y., Chopra, A. P., Rosenhouse-Dantsker, A., Kowalsky, G. B., Logothetis, D. E., Levitan, I. <strong>Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol.</strong> Proc. Nat. Acad. Sci. 106: 8055-8060, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19416905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19416905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19416905[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.0809847106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19416905">Epshtein et al. (2009)</a> noted that K(+) channel activation is suppressed by elevated membrane cholesterol. By mutating specific residues in mouse Kir2.1, they found that cholesterol sensitivity was due to a subset of channel-activating PIP2-sensitive residues within the CD loop in the C-terminal cytosolic domain. PIP2-sensitive residues outside this loop and lipid-facing residues of the outer helix transmembrane domain were not involved in cholesterol sensitivity. Mutations of the critical residues did not interfere with Kir2.1-PIP2 interaction and did not alter the targeting of Kir2.1 to specific membrane domains. <a href="#10" class="mim-tip-reference" title="Epshtein, Y., Chopra, A. P., Rosenhouse-Dantsker, A., Kowalsky, G. B., Logothetis, D. E., Levitan, I. <strong>Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol.</strong> Proc. Nat. Acad. Sci. 106: 8055-8060, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19416905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19416905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19416905[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.0809847106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19416905">Epshtein et al. (2009)</a> hypothesized that these residues may contribute to the docking of the Kir2.1 C terminus to the inner membrane leaflet, facilitating its interaction with membrane cholesterol, and possibly stabilizing the channel in the closed conformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19416905" 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>Atrial fibrillation is accompanied by increased inward rectifier K+ currents along with increased expression of the principal K+ channel subunit KCNJ2. <a href="#16" class="mim-tip-reference" title="Luo, X., Pan, Z., Shan, H., Xiao, J., Sun, X., Wang, N., Lin, H., Xiao, L., Maguy, A., Qi, X.-Y., Li, Y., Gao, X., and 11 others. <strong>MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation.</strong> J. Clin. Invest. 123: 1939-1951, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23543060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23543060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23543060[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI62185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23543060">Luo et al. (2013)</a> found that MIR26 (see MIR26A1, <a href="/entry/612151">612151</a>) expression was downregulated concomitant with upregulation of KCNJ2 in atrial samples of patients with atrial fibrillation and in canine and mouse models. They identified a MIR26 target sequence in the KCNJ2 mRNA. Knockdown or inhibition of Mir26, or mutation of the Mir26-binding site in Kcnj2 in rat cardiomyocytes, enhanced Kcnj2 expression and confirmed Kcnj2 as a Mir26 target. Conversely, expression of Kcnj2-specific oligonucleotides masking the Mir26-binding site elevated Kcnj2 expression and increased vulnerability of mice to atrial fibrillation. <a href="#16" class="mim-tip-reference" title="Luo, X., Pan, Z., Shan, H., Xiao, J., Sun, X., Wang, N., Lin, H., Xiao, L., Maguy, A., Qi, X.-Y., Li, Y., Gao, X., and 11 others. <strong>MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation.</strong> J. Clin. Invest. 123: 1939-1951, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23543060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23543060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23543060[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI62185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23543060">Luo et al. (2013)</a> further found that NFAT (see NFATC1, <a href="/entry/600489">600489</a>) negatively regulated Mir26 transcription and consequently elevated Kcnj2 expression. The authors concluded that downregulated MIR26 expression contributes to development of atrial fibrillation due to enhanced KCNJ2 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23543060" 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>Andersen Cardiodysrhythmic Periodic Paralysis</em></strong></p><p>
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Andersen cardiodysrhythmic periodic paralysis (<a href="/entry/170390">170390</a>), also known as Andersen syndrome, Andersen-Tawil syndrome, or long QT syndrome-7 (LQT7), is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. Using 400 polymorphic markers across the entire genome in 15 individuals of a kindred with Andersen syndrome, <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> mapped the disease locus to 17q23 (maximum lod of 3.23 at theta of 0 for D17S949) near the KCNJ2 gene. They identified heterozygosity for a missense mutation in the KCNJ2 gene in the linked family and 8 additional heterozygous mutations in unrelated patients. Expression of 2 of these mutations (D71V, <a href="#0001">600681.0001</a>, and R218W, <a href="#0002">600681.0002</a>) in Xenopus oocytes revealed loss of function and a dominant-negative effect in KCNJ2 current as assayed by voltage-clamp. <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> concluded that mutations in the KCNJ2 gene cause Andersen syndrome, and the findings suggested that KCNJ2 plays an important role in developmental signaling in addition to its function in controlling cell excitability in skeletal muscle and heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371347" 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="#24" class="mim-tip-reference" title="Tristani-Firouzi, M., Jensen, J. L., Donaldson, M. R., Sansone, V., Meola, G., Hahn, A., Bendahhou, S., Kwiecinski, H., Fidzianska, A., Plaster, N., Fu, Y.-H., Ptacek, L. J., Tawil, R. <strong>Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).</strong> J. Clin. Invest. 110: 381-388, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12163457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163457">Tristani-Firouzi et al. (2002)</a> identified 3 novel Andersen syndrome-associated mutations in the KCNJ2 gene (<a href="#0007">600681.0007</a>-<a href="#0009">600681.0009</a>) and presented extensive clinical and in vitro electrophysiologic studies on a total of 17 kindreds with 10 different mutations. All these mutations in KCNJ2 caused dominant-negative suppression of Kir2.1 channel function. There was significant overlap in the extent of dominant-negative effect as well as overlap in clinical phenotype. LQT and ventricular arrhythmias were common in mutation carriers. Unlike other forms of inherited LQTS, sudden death had not been reported in Andersen syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163457" 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>Among 17 unrelated probands with clinical symptoms of Andersen syndrome, <a href="#8" class="mim-tip-reference" title="Donaldson, M. R., Jensen, J. L., Tristani-Firouzi, M., Tawil, R., Bendahhou, S., Suarez, W. A., Cobo, A. M., Poza, J. J., Behr, E., Wagstaff, J., Szepetowski, P., Pereira, S., Mozaffar, T., Escolar, D. M., Fu, Y.-H., Ptacek, L. J. <strong>PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.</strong> Neurology 60: 1811-1816, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796536</a>] [<a href="https://doi.org/10.1212/01.wnl.0000072261.14060.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796536">Donaldson et al. (2003)</a> identified 8 different mutations, including 6 novel mutations, in the KCNJ2 gene in 9 probands. Six probands possessed mutations of residues implicated in binding membrane-associated PIP2. Including previous reports, the authors determined that mutations in PIP2-related residues accounted for disease in 18 of 29 (62%) reported families with KCNJ2-related ATS. <a href="#8" class="mim-tip-reference" title="Donaldson, M. R., Jensen, J. L., Tristani-Firouzi, M., Tawil, R., Bendahhou, S., Suarez, W. A., Cobo, A. M., Poza, J. J., Behr, E., Wagstaff, J., Szepetowski, P., Pereira, S., Mozaffar, T., Escolar, D. M., Fu, Y.-H., Ptacek, L. J. <strong>PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.</strong> Neurology 60: 1811-1816, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796536</a>] [<a href="https://doi.org/10.1212/01.wnl.0000072261.14060.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796536">Donaldson et al. (2003)</a> found no phenotypic differences between patients with mutations in the PIP2-related residues and those with mutations elsewhere in the gene. The authors suggested that genetic heterogeneity likely exists for this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12796536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Davies, N. P., Imbrici, P., Fialho, D., Herd, C., Bilsland, L. G., Weber, A., Mueller, R., Hilton-Jones, D., Ealing, J., Boothman, B. R., Giunti, P., Parsons, L. M., Thomas, M., Manzur, A. Y., Jurkat-Rott, K., Lehmann-Horn, F., Chinnery, P. F., Rose, M., Kullmann, D. M., Hanna, M. G. <strong>Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation.</strong> Neurology 65: 1083-1089, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16217063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16217063</a>] [<a href="https://doi.org/10.1212/01.wnl.0000178888.03767.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16217063">Davies et al. (2005)</a> identified 9 different pathogenic mutations in the KCNJ2 gene, including 6 novel mutations, in 22 affected individuals from 11 unrelated families with Andersen-Tawil syndrome. In vitro functional expression studies of 5 of the mutant proteins showed a dominant-negative effect on the wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16217063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 affected members of a family with Andersen syndrome, <a href="#14" class="mim-tip-reference" title="Lu, C.-W., Lin, J.-H., Rajawat, Y. S., Jerng, H., Rami, T. G., Sanchez, X., DeFreitas, G., Carabello, B., DeMayo, F., Kearney, D. L., Miller, G., Li, H., Pfaffinger, P. J., Bowles, N. E., Khoury, D. S., Towbin, J. A. <strong>Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome.</strong> J. Med. Genet. 43: 653-659, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16571646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16571646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16571646[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/10.1136/jmg.2006.040816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16571646">Lu et al. (2006)</a> identified heterozygosity for a missense mutation in the KCNJ2 gene (T75R; <a href="#0011">600681.0011</a>), located in the highly conserved cytoplasmic N-terminal domain. In vitro studies revealed that the mutant channel was nonfunctional, and T75R transgenic mice had bidirectional ventricular tachycardia after induction and longer QT intervals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16571646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Choi, B.-O., Kim, J., Suh, B. C., Yu, J. S., Sunwoo, I. N., Kim, S. J., Kim, G. H., Chung, K. W. <strong>Mutations of KCNJ2 gene associated with Andersen-Tawil syndrome in Korean families.</strong> J. Hum. Genet. 52: 280-283, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17211524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17211524</a>] [<a href="https://doi.org/10.1007/s10038-006-0100-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17211524">Choi et al. (2007)</a> identified 2 different heterozygous missense mutations in the KCNJ2 gene in affected members of 2 Korean families with Andersen-Tawil syndrome. The authors stated that this was the first report of causative mutations in KCNJ2 in Korean ATS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17211524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated probands with periodic paralysis and cardiac dysrhythmias, who were known to be negative for common CACNA1S and SCN4A mutations causing hypokalemic periodic paralysis, <a href="#3" class="mim-tip-reference" title="Bendahhou, S., Fournier, E., Gallet, S., Menard, D., Larroque, M.-M., Barhanin, J. <strong>Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred.</strong> Hum. Molec. Genet. 16: 900-906, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17324964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17324964</a>] [<a href="https://doi.org/10.1093/hmg/ddm034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17324964">Bendahhou et al. (2007)</a> identified heterozygosity for 2 different missense mutations in the KCNJ2 gene (<a href="#0012">600681.0012</a> and <a href="#0013">600681.0013</a>, respectively). <a href="#3" class="mim-tip-reference" title="Bendahhou, S., Fournier, E., Gallet, S., Menard, D., Larroque, M.-M., Barhanin, J. <strong>Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred.</strong> Hum. Molec. Genet. 16: 900-906, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17324964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17324964</a>] [<a href="https://doi.org/10.1093/hmg/ddm034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17324964">Bendahhou et al. (2007)</a> noted that except for a small chin in 1 proband, there were no dysmorphic features in these families, and suggested that KCNJ2 should be screened in patients with periodic paralysis even when the classic dysmorphic features of Andersen syndrome are not present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17324964" 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>Short QT Syndrome 3</em></strong></p><p>
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In a 5-year-old girl and her father with short QT syndrome-3 (SQT3; <a href="/entry/609622">609622</a>), <a href="#21" class="mim-tip-reference" title="Priori, S. G., Pandit, S. V., Rivolta, I., Berenfeld, O., Ronchetti, E., Dhamoon, A., Napolitano, C., Anumonwo, J., Raffaele di Barletta, M., Gudapakkam, S., Bosi, G., Stramba-Badiale, M., Jalife, J. <strong>A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.</strong> Circ. Res. 96: 800-807, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761194</a>] [<a href="https://doi.org/10.1161/01.RES.0000162101.76263.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761194">Priori et al. (2005)</a> identified a missense mutation in the KCNJ2 gene (D172N; <a href="#0010">600681.0010</a>). Functional studies revealed a significant increase in the outward component of the I-V relation of I(K1). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15761194" 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 8-year-old Japanese girl with a markedly short QT interval, <a href="#11" class="mim-tip-reference" title="Hattori, T., Makiyama, T., Akao, M., Ehara, E., Ohno, S., Iguchi, M., Nishio, Y., Sasaki, K., Itoh, H., Yokode, M., Kita, T., Horie, M., Kimura, T. <strong>A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.</strong> Cardiovasc. Res. 93: 666-673, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22155372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22155372</a>] [<a href="https://doi.org/10.1093/cvr/cvr329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22155372">Hattori et al. (2012)</a> screened known cardiac ion channel genes and identified heterozygosity for a missense mutation in the KCNJ2 gee (M301K; <a href="#0015">600681.0015</a>). Family DNA was unavailable for study, but the variant was not found in 400 Japanese control alleles. Functional assays revealed that homozygous mutant channels were completely nonfunctional, whereas heterozygous M301K channels showed impaired inward rectification resulting in larger outward currents, which the authors stated was a novel mechanism predisposing to SQTS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22155372" 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 11-year-old boy with recurrent paroxysmal atrial fibrillation and short QT interval, <a href="#6" class="mim-tip-reference" title="Deo, M., Ruan, Y., Pandit, S. V., Shah, K., Berenfeld, O., Blaufox, A., Cerrone, M., Noujaim, S. F., Denegri, M., Jalife, J., Priori, S. G. <strong>KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.</strong> Proc. Nat. Acad. Sci. 110: 4291-4296, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23440193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23440193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23440193[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.1218154110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23440193">Deo et al. (2013)</a> identified heterozygosity for a missense mutation in the KCNJ2 gene (E299V; <a href="#0016">600681.0016</a>). Functional analysis revealed that the E299V mutation abolishes inward rectification; heterozygous channels showed severely impaired inward rectification, resulting in a large outward current during the early phase of the action potential that markedly shortens its duration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23440193" 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 Atrial Fibrillation 9</em></strong></p><p>
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In affected members of a Chinese family segregating autosomal dominant atrial fibrillation (ATFB9; <a href="/entry/613980">613980</a>), <a href="#26" class="mim-tip-reference" title="Xia, M., Jin, Q., Bendahhou, S., He, Y., Larroque, M.-M., Chen, Y., Zhou, Q., Yang, Y., Liu, Y., Liu, B., Zhu, Q., Zhou, Y., and 12 others. <strong>A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.</strong> Biochem. Biophys. Res. Commun. 332: 1012-1019, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15922306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15922306</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.05.054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15922306">Xia et al. (2005)</a> identified heterozygosity for a mutation in the KCNJ2 gene (V93I; <a href="#0014">600681.0014</a>). Functional analysis revealed that the V93I mutation has a gain-of-function effect on the Kir2.1 current, in contrast to the loss of function observed with previously reported KCNJ2 mutations associated with the Andersen periodic paralysis syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15922306" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation near the KCNJ2 gene and susceptibility to thyrotoxic periodic paralysis, see TTPP3 (<a href="/entry/614834">614834</a>).</p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>16 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600681[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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<p>In the affected individuals of a pedigree (K4415) with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> identified a heterozygous (dominant) mutation in the KCNJ2 gene. The A-to-T transversion at nucleotide 440 resulted in an asp71-to-val substitution in the N terminus of the KCNJ2 protein. The mutation was not found in 100 unaffected and unrelated individuals. Expression of this mutation in Xenopus oocytes revealed loss of function and a dominant-negative effect in KCNJ2 current as assayed by voltage-clamp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371347" 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">rs104894578 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894578;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=rs104894578" 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=rs104894578" 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=RCV000009474 OR RCV000058326 OR RCV000170982 OR RCV000684775 OR RCV004018605" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009474, RCV000058326, RCV000170982, RCV000684775, RCV004018605" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009474...</a>
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<p>In the affected individuals of 4 different pedigrees (K2679, K6515, K2681, and K2401) with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> identified a heterozygous (dominant) mutation in the KCNJ2 gene. The C-to-T transition at nucleotide 880 resulted in an arg218-to-trp (R218W) substitution within the C-terminal interaction domain of the KCNJ2 protein. The mutation occurred de novo in 3 pedigrees, and it was not found in 100 unaffected and unrelated individuals. Expression of this mutation in Xenopus oocytes revealed loss of function and a dominant-negative effect in KCNJ2 current as assayed by voltage-clamp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371347" 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">rs104894579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894579;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=rs104894579" 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=rs104894579" 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=RCV000009475 OR RCV000058332 OR RCV000170987 OR RCV002512943 OR RCV004629139" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009475, RCV000058332, RCV000170987, RCV002512943, RCV004629139" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009475...</a>
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<p>In the affected individuals of 2 different pedigrees (K3677 and K3387) with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> identified a heterozygous (dominant) mutation in the KCNJ2 gene. The G-to-T transversion at nucleotide 1127 resulted in a gly300-to-val substitution. This mutation was not found in 100 unaffected and unrelated individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371347" 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>.0004 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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">rs2144376746 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2144376746;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=rs2144376746" 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=rs2144376746" 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=RCV000009476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009476</a>
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<p>In an affected individual of a pedigree (K2281) with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> identified a heterozygous (dominant) in-frame deletion of 12 nucleotides in the KCNJ2 gene, resulting in the deletion of amino acids 95 to 98 in the M1 transmembrane segment. This mutation was not found in 100 unaffected and unrelated individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371347" 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 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
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KCNJ2, 6-BP DEL, NT1167
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2074390325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2074390325;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=rs2074390325" 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=rs2074390325" 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=RCV001260872 OR RCV001379609" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001260872, RCV001379609" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001260872...</a>
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<p>In an affected individual of a pedigree (K5768) with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#19" class="mim-tip-reference" title="Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others. <strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong> Cell 105: 511-519, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371347</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371347">Plaster et al. (2001)</a> identified a heterozygous (dominant) in-frame deletion of 6 nucleotides in the KCNJ2 gene, resulting in the deletion of amino acids 314 to 315. This mutation occurred de novo in this family and was not found in 100 unaffected and unrelated individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371347" 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> rs104894580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894580;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/rs104894580?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=rs104894580" 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=rs104894580" 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=RCV000009478 OR RCV000058294 OR RCV000170971 OR RCV000763415 OR RCV000814909 OR RCV001000954 OR RCV002415408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009478, RCV000058294, RCV000170971, RCV000763415, RCV000814909, RCV001000954, RCV002415408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009478...</a>
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<p>See Andersen cardiodysrhythmic periodic paralysis (<a href="/entry/170390">170390</a>). <a href="#2" class="mim-tip-reference" title="Andelfinger, G., Tapper, A. R., Welch, R. C., Vanoye, C. G., George, A. L., Jr., Benson, D. W. <strong>KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes.</strong> Am. J. Hum. Genet. 71: 663-668, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12148092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12148092</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12148092[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12148092">Andelfinger et al. (2002)</a> identified a heterozygous missense mutation (arg67 to trp; R67W) in the KCNJ2 gene in 41 members of a kindred with ventricular arrhythmias (13 of 16 female members, 81%) and periodic paralysis (10 of 25 male members, 40%) segregating as autosomal dominant traits with sex-specific variable expressivity. Some mutation carriers exhibited dysmorphic features, including hypertelorism, small mandible, syndactyly, clinodactyly, cleft palate, and scoliosis, which, together with cardiodysrhythmic periodic paralysis, constitute Andersen syndrome (<a href="/entry/170390">170390</a>). However, no individual exhibited all manifestations of Andersen syndrome, and this diagnosis was not considered in the proband until other family members were examined. Other features seen in this kindred included unilateral dysplastic kidney and cardiovascular malformation (i.e., bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis), which had not previously been associated with Andersen syndrome. Nonspecific electrocardiographic abnormalities were identified in some individuals, but none had a prolonged QT interval. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12148092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Andelfinger, G., Tapper, A. R., Welch, R. C., Vanoye, C. G., George, A. L., Jr., Benson, D. W. <strong>KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes.</strong> Am. J. Hum. Genet. 71: 663-668, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12148092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12148092</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12148092[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12148092">Andelfinger et al. (2002)</a> stated that sex specificity of cardiac arrhythmias and periodic paralysis had not previously been described in Andersen syndrome. However, there had been an increasing recognition of specific electrocardiographic and electrophysiologic differences--for example, resting heart rate and corrected QT intervals--between males and females, but the precise way in which sex and gonadal steroids contribute to these differences was not known (<a href="#18" class="mim-tip-reference" title="Pham, T. V., Rosen, M. R. <strong>Sex, hormones, and repolarization.</strong> Cardiovasc. Res. 53: 740-751, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11861044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11861044</a>] [<a href="https://doi.org/10.1016/s0008-6363(01)00429-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11861044">Pham and Rosen, 2002</a>; <a href="#25" class="mim-tip-reference" title="Wolbrette, D., Naccarelli, G., Curtis, A., Lehmann, M., Kadish, A. <strong>Gender differences in arrhythmias.</strong> Clin. Cardiol. 25: 49-56, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11841151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11841151</a>] [<a href="https://doi.org/10.1002/clc.4950250203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11841151">Wolbrette et al., 2002</a>). Female subjects with the R67W mutation typically noted onset of ventricular arrhythmia after age 10 years. An increased incidence is usually reported during pregnancy, but female subjects with R67W reported reduced ventricular arrhythmias during pregnancy and after age 55 years, coinciding with menopause. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11841151+11861044+12148092" 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">rs104894581 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894581;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=rs104894581" 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=rs104894581" 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=RCV000009479 OR RCV000058319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009479, RCV000058319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009479...</a>
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<p>In a kindred with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#24" class="mim-tip-reference" title="Tristani-Firouzi, M., Jensen, J. L., Donaldson, M. R., Sansone, V., Meola, G., Hahn, A., Bendahhou, S., Kwiecinski, H., Fidzianska, A., Plaster, N., Fu, Y.-H., Ptacek, L. J., Tawil, R. <strong>Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).</strong> J. Clin. Invest. 110: 381-388, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12163457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163457">Tristani-Firouzi et al. (2002)</a> identified a C-to-T transition at nucleotide 785 of the KCNJ2 gene, which resulted in a pro186-to-leu (P186L) amino acid substitution. This mutation alters an amino acid of a PKKR motif (amino acids 186-189), a C-terminal motif implicated in binding the signaling phospholipid PIP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163457" 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">rs104894582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894582;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=rs104894582" 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=rs104894582" 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=RCV000009480 OR RCV000058333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009480, RCV000058333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009480...</a>
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<p>In a kindred with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#24" class="mim-tip-reference" title="Tristani-Firouzi, M., Jensen, J. L., Donaldson, M. R., Sansone, V., Meola, G., Hahn, A., Bendahhou, S., Kwiecinski, H., Fidzianska, A., Plaster, N., Fu, Y.-H., Ptacek, L. J., Tawil, R. <strong>Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).</strong> J. Clin. Invest. 110: 381-388, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12163457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163457">Tristani-Firouzi et al. (2002)</a> found a G-to-A transition at nucleotide 1132 of the KCNJ2 gene, resulting in a val302-to-met (V302M) amino acid change. This mutation lies in a C-terminal region that may be responsible for channel subunit assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163457" 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">rs104894583 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894583;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=rs104894583" 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=rs104894583" 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=RCV000009481 OR RCV000058324" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009481, RCV000058324" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009481...</a>
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<p>In a kindred with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#24" class="mim-tip-reference" title="Tristani-Firouzi, M., Jensen, J. L., Donaldson, M. R., Sansone, V., Meola, G., Hahn, A., Bendahhou, S., Kwiecinski, H., Fidzianska, A., Plaster, N., Fu, Y.-H., Ptacek, L. J., Tawil, R. <strong>Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).</strong> J. Clin. Invest. 110: 381-388, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12163457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163457">Tristani-Firouzi et al. (2002)</a> identified an A-to-C transversion at nucleotide 874 of the KCNJ2 gene, which resulted in an asn261-to-his (N216H) amino acid change. This mutation lies within a C-terminal region (amino acids 207-246) thought to be involved in PIP2 interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163457" 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">rs104894584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894584;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=rs104894584" 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=rs104894584" 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=RCV000009482 OR RCV000058318 OR RCV001384722" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009482, RCV000058318, RCV001384722" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009482...</a>
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<p>In a 5-year-old girl and her father with short QT syndrome-3 (SQT3; <a href="/entry/609622">609622</a>), <a href="#21" class="mim-tip-reference" title="Priori, S. G., Pandit, S. V., Rivolta, I., Berenfeld, O., Ronchetti, E., Dhamoon, A., Napolitano, C., Anumonwo, J., Raffaele di Barletta, M., Gudapakkam, S., Bosi, G., Stramba-Badiale, M., Jalife, J. <strong>A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.</strong> Circ. Res. 96: 800-807, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761194</a>] [<a href="https://doi.org/10.1161/01.RES.0000162101.76263.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761194">Priori et al. (2005)</a> identified a 514G-A transition in the KCNJ2 gene, resulting in an asp172-to-asn (D172N) substitution. The mutation was not found in unaffected family members. Functional studies revealed a significant increase in the outward component of the I-V relation of I(K1). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15761194" 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>Variant Function</em></strong></p><p>
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Using 2D ventricular cell and 3D tissue models, <a href="#1" class="mim-tip-reference" title="Adeniran, I., El Harchi, A., Hancox, J. C., Zhang, H. <strong>Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling.</strong> Cardiovasc. Res. 94: 66-76, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22308236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22308236</a>] [<a href="https://doi.org/10.1093/cvr/cvs082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22308236">Adeniran et al. (2012)</a> studied the effects of the Kir2.1 D172N mutation. They found that the D172N mutation abbreviates the action potential duration (APD) at 90% of repolarization (APD90) and steepens the restitution of APD and effective refractory period (ERP) curves, thus increasing susceptibility to arrhythmia; shortens the QT interval and alters the morphology of T-waves, which were tall, peaked, and asymmetric, similar to those of the <a href="#21" class="mim-tip-reference" title="Priori, S. G., Pandit, S. V., Rivolta, I., Berenfeld, O., Ronchetti, E., Dhamoon, A., Napolitano, C., Anumonwo, J., Raffaele di Barletta, M., Gudapakkam, S., Bosi, G., Stramba-Badiale, M., Jalife, J. <strong>A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.</strong> Circ. Res. 96: 800-807, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761194</a>] [<a href="https://doi.org/10.1161/01.RES.0000162101.76263.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761194">Priori et al. (2005)</a> proband; augments the transmural dispersion of APD90 across the ventricular wall, which leads to the increase, at some localized regions, of the temporal vulnerability of the tissue to the genesis of unidirectional conduction by premature excitation; reduces the minimal substrate size of tissue required to initiate and maintain reentry; and stabilizes and accelerates reentrant excitation waves. The authors concluded that the D172N mutant results in increased transmural APD dispersion that increases tissue vulnerability to the genesis of reentry with premature exitation, and also shortens the ventricular tissue ERP, which facilitates the maintenance of reentry once it has been initiated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22308236+15761194" 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>.0011 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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">rs104894585 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894585;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=rs104894585" 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=rs104894585" 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=RCV000009483 OR RCV000058301 OR RCV001851764" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009483, RCV000058301, RCV001851764" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009483...</a>
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<p>In 3 affected members of a family with Andersen syndrome (<a href="/entry/170390">170390</a>), <a href="#14" class="mim-tip-reference" title="Lu, C.-W., Lin, J.-H., Rajawat, Y. S., Jerng, H., Rami, T. G., Sanchez, X., DeFreitas, G., Carabello, B., DeMayo, F., Kearney, D. L., Miller, G., Li, H., Pfaffinger, P. J., Bowles, N. E., Khoury, D. S., Towbin, J. A. <strong>Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome.</strong> J. Med. Genet. 43: 653-659, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16571646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16571646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16571646[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/10.1136/jmg.2006.040816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16571646">Lu et al. (2006)</a> identified heterozygosity for a 224C-G transversion, resulting in a thr75-to-arg (T75R) substitution at a highly conserved codon in the cytoplasmic N-terminal portion of Kir2.1. The mutation was not found in 2 unaffected family members or in 100 unrelated controls. Although the mutant protein was able to coassemble and traffic to the cell membrane in mouse atrial cardiomyocytes, voltage clamp analysis in Xenopus oocytes revealed that the mutant channel was nonfunctional; upon coexpression of mutant and wildtype cRNA in Xenopus oocytes, the K(+) current was completely lost, demonstrating the strong dominant-negative effect of the T75R mutant. Transgenic T75R mice had bidirectional ventricular tachycardia after induction and longer QT intervals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16571646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
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KCNJ2, CYS54PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199473650 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473650;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=rs199473650" 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=rs199473650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023027 OR RCV000058293" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023027, RCV000058293" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023027...</a>
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<p>In a 19-year-old man with periodic paralysis and cardiac dysrhythmias (<a href="/entry/170390">170390</a>), triggered by use of corticosteroids on at least 2 occasions, <a href="#3" class="mim-tip-reference" title="Bendahhou, S., Fournier, E., Gallet, S., Menard, D., Larroque, M.-M., Barhanin, J. <strong>Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred.</strong> Hum. Molec. Genet. 16: 900-906, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17324964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17324964</a>] [<a href="https://doi.org/10.1093/hmg/ddm034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17324964">Bendahhou et al. (2007)</a> identified heterozygosity for a 489G-T transversion in the KCNJ2 gene, resulting in a cys54-to-phe (C54F) substitution at a conserved residue in the N terminus. Functional expression in mammalian cells revealed loss of function when the mutant was expressed alone and a dominant-negative effect when expressed with wildtype channels; however, channel trafficking and assembly were not affected. The proband's unaffected brother and father also carried the mutation. Aside from a small chin in the proband, there were no dysmorphic features in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17324964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
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KCNJ2, THR305PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199473387 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473387;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=rs199473387" 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=rs199473387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023028 OR RCV000058335" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023028, RCV000058335" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023028...</a>
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<span class="mim-text-font">
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<p>In a 23-year-old woman with periodic paralysis and cardiac dysrhythmias that began in childhood (<a href="/entry/170390">170390</a>), <a href="#3" class="mim-tip-reference" title="Bendahhou, S., Fournier, E., Gallet, S., Menard, D., Larroque, M.-M., Barhanin, J. <strong>Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred.</strong> Hum. Molec. Genet. 16: 900-906, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17324964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17324964</a>] [<a href="https://doi.org/10.1093/hmg/ddm034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17324964">Bendahhou et al. (2007)</a> identified heterozygosity for a 1141A-C transversion in the KCNJ2 gene, resulting in a thr305-to-pro (T305P) substitution at a conserved residue in the C terminus. Functional expression in mammalian cells revealed loss of function when the mutant was expressed alone and a dominant-negative effect when expressed with wildtype channels; however, channel trafficking and assembly were not affected. There were no dysmorphic features in the proband. Her mother, maternal aunt, and maternal grandmother had a history of cardiac dysrhythmias, and the grandmother had a pacemaker. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17324964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<strong>.0014 ATRIAL FIBRILLATION, FAMILIAL, 9</strong>
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KCNJ2, VAL93ILE
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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> rs147750704 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147750704;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/rs147750704?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=rs147750704" 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=rs147750704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023029 OR RCV000148540 OR RCV000170978 OR RCV000544361 OR RCV001127504 OR RCV001127505 OR RCV002433466 OR RCV003318334" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023029, RCV000148540, RCV000170978, RCV000544361, RCV001127504, RCV001127505, RCV002433466, RCV003318334" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023029...</a>
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<p>In affected members of a Chinese family with atrial fibrillation (ATFB9; <a href="/entry/613980">613980</a>), <a href="#26" class="mim-tip-reference" title="Xia, M., Jin, Q., Bendahhou, S., He, Y., Larroque, M.-M., Chen, Y., Zhou, Q., Yang, Y., Liu, Y., Liu, B., Zhu, Q., Zhou, Y., and 12 others. <strong>A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.</strong> Biochem. Biophys. Res. Commun. 332: 1012-1019, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15922306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15922306</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.05.054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15922306">Xia et al. (2005)</a> identified heterozygosity for a 227G-A transition in the KCNJ2 gene, resulting in a val93-to-ile (V93I) substitution at a highly conserved residue. The mutation was not found in 420 controls. Patch-clamp studies in COS-7 and HEK293 cells demonstrated that the V93I mutation has a gain-of-function effect on Kir2.1 channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15922306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<strong>.0015 SHORT QT SYNDROME 3</strong>
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KCNJ2, MET301LYS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003481514" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003481514" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003481514</a>
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<p>In an 8-year-old Japanese girl with a markedly short QT interval (SQT3; <a href="/entry/609622">609622</a>), <a href="#11" class="mim-tip-reference" title="Hattori, T., Makiyama, T., Akao, M., Ehara, E., Ohno, S., Iguchi, M., Nishio, Y., Sasaki, K., Itoh, H., Yokode, M., Kita, T., Horie, M., Kimura, T. <strong>A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.</strong> Cardiovasc. Res. 93: 666-673, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22155372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22155372</a>] [<a href="https://doi.org/10.1093/cvr/cvr329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22155372">Hattori et al. (2012)</a> identified heterozygosity for a c.902T-A transversion in the KCNJ2 gene, resulting in a met301-to-lys (M301K) substitution at a highly conserved residue within a pore-facing loop region in the C-terminal cytoplasmic domain. Family DNA was unavailable for study, but the variant was not found in 400 Japanese control alleles. Functional characterization of mutant channels in HEK293 cells showed that homozygous mutant channels were entirely nonfunctional, whereas heterozygous channels had very weak inward rectification, which resulted in significantly larger outward current densities at potentials between -30 and +100 mV. Studies using transiently transfected neonatal rat ventricular myocytes demonstrated that significant increases in outward currents within the voltage range of action potentials (APs) shortened the AP duration by accelerating membrane repolarization. Whole-cell patch-clamp recordings revealed the importance of a neutral amino acid residue like methionine at position 301 for generating Kir2.1 inward rectification: substituting a different neutral (alanine) or a positively charged (arginine) residue at M301 resulted in function similar to wildtype with the former, and attenuated inward rectification with the latter, similar to that seen with the M301K mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22155372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<strong>.0016 SHORT QT SYNDROME 3</strong>
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KCNJ2, GLU299VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205817;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=rs786205817" 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=rs786205817" 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=RCV000170986 OR RCV003482239" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170986, RCV003482239" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170986...</a>
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<p>In an 11-year-old boy with recurrent paroxysmal atrial fibrillation and short QT interval (SQT3; <a href="/entry/609622">609622</a>), <a href="#6" class="mim-tip-reference" title="Deo, M., Ruan, Y., Pandit, S. V., Shah, K., Berenfeld, O., Blaufox, A., Cerrone, M., Noujaim, S. F., Denegri, M., Jalife, J., Priori, S. G. <strong>KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.</strong> Proc. Nat. Acad. Sci. 110: 4291-4296, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23440193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23440193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23440193[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.1218154110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23440193">Deo et al. (2013)</a> identified heterozygosity for a de novo c.896A-T transversion in the KCNJ2 gene, resulting in a glu299-to-val (E299V) substitution at a highly conserved residue within the Kir2.1 cytoplasmic terminal. The mutation was not found in his parents or in 400 control individuals. Functional analysis in HEK293 cells showed a significant reduction of the inward current with the heterozygous E299V mutant channel compared to wildtype, with major impairment at more positive voltages. Action potential clamp recordings confirmed severely impaired inward rectification with the E299V mutant, resulting in a large outward current during the early phase of the action potential that dramatically shortens the action potential duration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23440193" 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 href="https://doi.org/10.1093/cvr/cvs082" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12148092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12148092</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12148092[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=12148092" 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/10.1086/342360" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17324964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17324964</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17324964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm034" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17211524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17211524</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17211524" 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/10.1007/s10038-006-0100-7" target="_blank">Full Text</a>]
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Davies, N. P., Imbrici, P., Fialho, D., Herd, C., Bilsland, L. G., Weber, A., Mueller, R., Hilton-Jones, D., Ealing, J., Boothman, B. R., Giunti, P., Parsons, L. M., Thomas, M., Manzur, A. Y., Jurkat-Rott, K., Lehmann-Horn, F., Chinnery, P. F., Rose, M., Kullmann, D. M., Hanna, M. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16217063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16217063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16217063" 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/10.1212/01.wnl.0000178888.03767.74" target="_blank">Full Text</a>]
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Deo, M., Ruan, Y., Pandit, S. V., Shah, K., Berenfeld, O., Blaufox, A., Cerrone, M., Noujaim, S. F., Denegri, M., Jalife, J., Priori, S. G.
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<strong>KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23440193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23440193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23440193[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=23440193" 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.1218154110" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(01)02202-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0809847106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/cvr/cvr329" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(02)00725-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2006.040816" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35101535" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI62185" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/419132b" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0008-6363(01)00429-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(01)00342-7" target="_blank">Full Text</a>]
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<strong>Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12032359[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=12032359" 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.102609499" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.RES.0000162101.76263.8c" target="_blank">Full Text</a>]
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<strong>Molecular cloning and expression of a human heart inward rectifier potassium channel.</strong>
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[<a href="https://doi.org/10.1097/00001756-199412000-00024" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0708153105" target="_blank">Full Text</a>]
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<a id="Tristani-Firouzi2002" class="mim-anchor"></a>
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<strong>Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).</strong>
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[<a href="https://doi.org/10.1172/JCI15183" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/clc.4950250203" target="_blank">Full Text</a>]
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<a id="Xia2005" class="mim-anchor"></a>
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Xia, M., Jin, Q., Bendahhou, S., He, Y., Larroque, M.-M., Chen, Y., Zhou, Q., Yang, Y., Liu, Y., Liu, B., Zhu, Q., Zhou, Y., and 12 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15922306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15922306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15922306" 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.2005.05.054" target="_blank">Full Text</a>]
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/02/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 03/09/2016<br>Marla J. F. O'Neill - updated : 5/17/2011<br>Marla J. F. O'Neill - updated : 1/20/2011<br>Patricia A. Hartz - updated : 8/20/2010<br>Patricia A. Hartz - updated : 3/12/2008<br>Marla J. F. O'Neill - updated : 5/29/2007<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Marla J. F. O'Neill - updated : 8/31/2006<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Cassandra L. Kniffin - updated : 8/11/2003<br>Dawn Watkins-Chow - updated : 12/18/2002<br>Dawn Watkins-Chow - updated : 11/14/2002<br>Ada Hamosh - updated : 9/30/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 6/17/2002<br>Ada Hamosh - updated : 10/23/2001<br>Stylianos E. Antonarakis - updated : 6/4/2001
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Creation Date:
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<span class="mim-text-font">
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Orest Hurko : 7/25/1995
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 04/29/2024
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carol : 01/03/2024<br>alopez : 01/02/2024<br>alopez : 03/09/2016<br>alopez : 9/26/2012<br>carol : 9/26/2012<br>wwang : 5/17/2011<br>terry : 5/17/2011<br>wwang : 2/2/2011<br>terry : 1/20/2011<br>wwang : 9/15/2010<br>terry : 8/20/2010<br>mgross : 3/13/2008<br>terry : 3/12/2008<br>wwang : 2/25/2008<br>wwang : 5/29/2007<br>wwang : 2/8/2007<br>ckniffin : 2/5/2007<br>wwang : 9/1/2006<br>terry : 8/31/2006<br>wwang : 9/30/2005<br>terry : 9/29/2005<br>terry : 9/29/2005<br>cwells : 8/20/2003<br>ckniffin : 8/11/2003<br>carol : 2/25/2003<br>carol : 2/25/2003<br>carol : 2/4/2003<br>alopez : 1/15/2003<br>alopez : 1/15/2003<br>terry : 1/2/2003<br>tkritzer : 12/18/2002<br>tkritzer : 12/18/2002<br>cwells : 11/14/2002<br>alopez : 10/1/2002<br>tkritzer : 9/30/2002<br>alopez : 9/20/2002<br>carol : 9/17/2002<br>cwells : 7/8/2002<br>terry : 6/17/2002<br>cwells : 10/24/2001<br>cwells : 10/24/2001<br>terry : 10/23/2001<br>mgross : 6/4/2001<br>mgross : 6/4/2001<br>terry : 7/7/1999<br>joanna : 5/8/1998<br>alopez : 2/9/1998<br>mark : 10/2/1995<br>mark : 7/25/1995
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<span class="mim-font">
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<strong>*</strong> 600681
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<h3>
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POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 2; KCNJ2
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<em>Alternative titles; symbols</em>
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HHIRK1<br />
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IRK1<br />
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KIR2.1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KCNJ2</em></strong>
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<strong>SNOMEDCT:</strong> 422348008;
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<strong>
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Cytogenetic location: 17q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:70,169,532-70,180,044 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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17q24.3
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Andersen syndrome
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170390
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Autosomal dominant
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3
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Atrial fibrillation, familial, 9
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613980
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Autosomal dominant
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3
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Short QT syndrome 3
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609622
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The KCNJ2 gene encodes the strong inward rectifier K+ channel protein Kir2.1 (summary by Deo et al., 2013). </p>
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<strong>Cloning and Expression</strong>
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<p>Raab-Graham et al. (1994) used low stringency colony hybridization with the complete coding region of the mouse IRK gene (Kubo et al., 1993) to isolate cDNA from human heart that encodes an inwardly rectifying potassium channel, KCNJ2. Raab-Graham et al. (1994) symbolized the gene HHIRK1. The cDNA encodes a 427-amino acid protein with 2 putative transmembrane domains and an H5 region. Expression of HHIRK1 in Xenopus oocytes demonstrated strong inward rectification that was blocked by both extracellular barium and cesium ions, and they measured a single channel conductance of 30 pS. Northern blot analysis demonstrated a single 5.5-kb transcript with high levels in heart, brain, placenta, lung, and skeletal muscle. Lower levels were present in kidney. The HHIRK1 message was found in all brain subregions tested, particularly in the caudate nucleus, corpus callosum, and substantia nigra. In regions of sequence overlap, HHIRK1 shares 66 to 67% identity with a small conductance human potassium channel (KCNJ4; 600504). Because of similarities in channel properties, Raab-Graham et al. (1994) suggested that HHIRK1 was the prominent cardiac inward rectifier. </p>
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<strong>Gene Structure</strong>
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<p>Derst et al. (2001) determined that the KCNJ2 gene contains 2 exons and spans approximately 10 kb. </p>
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<strong>Mapping</strong>
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<p>Raab-Graham et al. (1994) mapped the HHIRK1 gene to human chromosome 17 by PCR amplification from a somatic cell hybrid panel. This location is consistent with the mapping of mouse IRK1 to a distal region of mouse chromosome 11 that shares homology with human chromosome 17. (See also KCNJ1, 600359). </p><p>By radiation hybrid analysis, electronic PCR, and sequence similarity to mapped BACs, Derst et al. (2001) mapped the KCNJ2 gene to chromosome 17q23.1-q24.2, separated by 34 kb from KCNJ16 (605722). </p>
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<strong>Biochemical Features</strong>
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<p>Doyle et al. (1998) determined the atomic structure of a bacterial potassium channel pore by means of x-ray crystallography. However, serious doubts were raised concerning whether the prokaryotic potassium channel pore actually represents those of eukaryotes. Lu et al. (2001) addressed this issue by substituting the prokaryotic potassium channel pore into eukaryotic voltage-gated (see 176260) and inward-rectifier potassium channels. The resulting chimeras retained the respective functional hallmarks of the eukaryotic channels, which indicates that the ion conduction pore is indeed conserved among potassium channels. </p><p>Preisig-Muller et al. (2002) demonstrated that heteromerization of Kir2.1 channels with wildtype Kir2.2 and Kir2.3 channels contributes to the phenotype of Andersen syndrome (170390). Coexpression of Kir2.1 mutants related to Andersen syndrome with wildtype Kir2.x channels showed a dominant negative effect, the extent of which varied between different mutants. The results suggested that differential tetramerization of the mutant allele of Kir2.1 with wildtype Kir2.1, Kir2.2, and Kir2.3 channels represents the molecular basis of the extraordinary pleiotropy and variability of Andersen syndrome. In addition to cardiac arrhythmias and periodic paralysis, dysmorphic features include scoliosis, low-set ears, wide-set eyes, small chin, and broad forehead, but expression of these traits is highly variable. </p><p>Miake et al. (2002) replaced 3 amino acid residues in the pore structure of Kir2.1 with alanine to create a dominant-negative construct that suppresses current when expressed with wildtype Kir2.1. When this construct was packaged with green fluorescent protein (GFP) into a bicistronic adenoviral vector and injected into the left ventricular cavity of guinea pigs during transient cross-clamping of the great vessels, transduction was successful in about 20% of ventricular myocytes, as determined by GFP fluorescence. This suppression of Kir2.1 converted quiescent heart muscle cells into pacemaker cells that successfully generated a spontaneous rhythmic electrical activity in the ventricle in vivo. Miake et al. (2002) concluded that genetically engineered pacemakers could be developed as a possible alternative to implantable electronic devices. </p>
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<strong>Gene Function</strong>
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<p>Inwardly rectifying potassium (Kir) channels are important regulators of resting membrane potential and cell excitability. The activity of Kir channels is critically dependent on the integrity of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). Using targeted mutations in KCNJ2 and KCNJ1 (600359), which the authors called Kir2.1 and Kir1.1, Lopes et al. (2002) identified residues important for PIP2 interaction. Mutations in residues associated with Andersen syndrome (170390) and Bartter syndrome (241200) decreased the strength of channel-PIP2 interactions. Lopes et al. (2002) concluded that a decrease in channel-PIP2 interactions underlies the molecular mechanism of Andersen and Bartter syndromes when these mutations are present in patients. </p><p>To gain insight into the mechanism of arrhythmia susceptibility, Tristani-Firouzi et al. (2002) used a ventricular myocyte model to simulate the effects of reduced Kir2.1. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular potassium ion, induced delayed afterdepolarizations and spontaneous arrhythmias. These findings suggested that the substrate for arrhythmia susceptibility in Andersen syndrome is distinct from that in the other forms of inherited long QT syndrome. </p><p>Although chloroquine is an important therapeutic agent for treatment of malaria, its safety margin is narrow. Chloroquine inhibits the cardiac inward rectifier K+ current and can induce lethal ventricular arrhythmias. Rodriguez-Menchaca et al. (2008) found that chloroquine blocked mouse Kir2.1 channels from the cytoplasmic surface in a voltage- and K(+)-dependent manner. Mutagenesis and molecular modeling showed that chloroquine did not penetrate deeply into the channel and was stabilized within the binding pocket by negatively charged and aromatic amino acids. </p><p>Epshtein et al. (2009) noted that K(+) channel activation is suppressed by elevated membrane cholesterol. By mutating specific residues in mouse Kir2.1, they found that cholesterol sensitivity was due to a subset of channel-activating PIP2-sensitive residues within the CD loop in the C-terminal cytosolic domain. PIP2-sensitive residues outside this loop and lipid-facing residues of the outer helix transmembrane domain were not involved in cholesterol sensitivity. Mutations of the critical residues did not interfere with Kir2.1-PIP2 interaction and did not alter the targeting of Kir2.1 to specific membrane domains. Epshtein et al. (2009) hypothesized that these residues may contribute to the docking of the Kir2.1 C terminus to the inner membrane leaflet, facilitating its interaction with membrane cholesterol, and possibly stabilizing the channel in the closed conformation. </p><p>Atrial fibrillation is accompanied by increased inward rectifier K+ currents along with increased expression of the principal K+ channel subunit KCNJ2. Luo et al. (2013) found that MIR26 (see MIR26A1, 612151) expression was downregulated concomitant with upregulation of KCNJ2 in atrial samples of patients with atrial fibrillation and in canine and mouse models. They identified a MIR26 target sequence in the KCNJ2 mRNA. Knockdown or inhibition of Mir26, or mutation of the Mir26-binding site in Kcnj2 in rat cardiomyocytes, enhanced Kcnj2 expression and confirmed Kcnj2 as a Mir26 target. Conversely, expression of Kcnj2-specific oligonucleotides masking the Mir26-binding site elevated Kcnj2 expression and increased vulnerability of mice to atrial fibrillation. Luo et al. (2013) further found that NFAT (see NFATC1, 600489) negatively regulated Mir26 transcription and consequently elevated Kcnj2 expression. The authors concluded that downregulated MIR26 expression contributes to development of atrial fibrillation due to enhanced KCNJ2 expression. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Andersen Cardiodysrhythmic Periodic Paralysis</em></strong></p><p>
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Andersen cardiodysrhythmic periodic paralysis (170390), also known as Andersen syndrome, Andersen-Tawil syndrome, or long QT syndrome-7 (LQT7), is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. Using 400 polymorphic markers across the entire genome in 15 individuals of a kindred with Andersen syndrome, Plaster et al. (2001) mapped the disease locus to 17q23 (maximum lod of 3.23 at theta of 0 for D17S949) near the KCNJ2 gene. They identified heterozygosity for a missense mutation in the KCNJ2 gene in the linked family and 8 additional heterozygous mutations in unrelated patients. Expression of 2 of these mutations (D71V, 600681.0001, and R218W, 600681.0002) in Xenopus oocytes revealed loss of function and a dominant-negative effect in KCNJ2 current as assayed by voltage-clamp. Plaster et al. (2001) concluded that mutations in the KCNJ2 gene cause Andersen syndrome, and the findings suggested that KCNJ2 plays an important role in developmental signaling in addition to its function in controlling cell excitability in skeletal muscle and heart. </p><p>Tristani-Firouzi et al. (2002) identified 3 novel Andersen syndrome-associated mutations in the KCNJ2 gene (600681.0007-600681.0009) and presented extensive clinical and in vitro electrophysiologic studies on a total of 17 kindreds with 10 different mutations. All these mutations in KCNJ2 caused dominant-negative suppression of Kir2.1 channel function. There was significant overlap in the extent of dominant-negative effect as well as overlap in clinical phenotype. LQT and ventricular arrhythmias were common in mutation carriers. Unlike other forms of inherited LQTS, sudden death had not been reported in Andersen syndrome. </p><p>Among 17 unrelated probands with clinical symptoms of Andersen syndrome, Donaldson et al. (2003) identified 8 different mutations, including 6 novel mutations, in the KCNJ2 gene in 9 probands. Six probands possessed mutations of residues implicated in binding membrane-associated PIP2. Including previous reports, the authors determined that mutations in PIP2-related residues accounted for disease in 18 of 29 (62%) reported families with KCNJ2-related ATS. Donaldson et al. (2003) found no phenotypic differences between patients with mutations in the PIP2-related residues and those with mutations elsewhere in the gene. The authors suggested that genetic heterogeneity likely exists for this disorder. </p><p>Davies et al. (2005) identified 9 different pathogenic mutations in the KCNJ2 gene, including 6 novel mutations, in 22 affected individuals from 11 unrelated families with Andersen-Tawil syndrome. In vitro functional expression studies of 5 of the mutant proteins showed a dominant-negative effect on the wildtype allele. </p><p>In 3 affected members of a family with Andersen syndrome, Lu et al. (2006) identified heterozygosity for a missense mutation in the KCNJ2 gene (T75R; 600681.0011), located in the highly conserved cytoplasmic N-terminal domain. In vitro studies revealed that the mutant channel was nonfunctional, and T75R transgenic mice had bidirectional ventricular tachycardia after induction and longer QT intervals. </p><p>Choi et al. (2007) identified 2 different heterozygous missense mutations in the KCNJ2 gene in affected members of 2 Korean families with Andersen-Tawil syndrome. The authors stated that this was the first report of causative mutations in KCNJ2 in Korean ATS patients. </p><p>In 2 unrelated probands with periodic paralysis and cardiac dysrhythmias, who were known to be negative for common CACNA1S and SCN4A mutations causing hypokalemic periodic paralysis, Bendahhou et al. (2007) identified heterozygosity for 2 different missense mutations in the KCNJ2 gene (600681.0012 and 600681.0013, respectively). Bendahhou et al. (2007) noted that except for a small chin in 1 proband, there were no dysmorphic features in these families, and suggested that KCNJ2 should be screened in patients with periodic paralysis even when the classic dysmorphic features of Andersen syndrome are not present. </p><p><strong><em>Short QT Syndrome 3</em></strong></p><p>
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In a 5-year-old girl and her father with short QT syndrome-3 (SQT3; 609622), Priori et al. (2005) identified a missense mutation in the KCNJ2 gene (D172N; 600681.0010). Functional studies revealed a significant increase in the outward component of the I-V relation of I(K1). </p><p>In an 8-year-old Japanese girl with a markedly short QT interval, Hattori et al. (2012) screened known cardiac ion channel genes and identified heterozygosity for a missense mutation in the KCNJ2 gee (M301K; 600681.0015). Family DNA was unavailable for study, but the variant was not found in 400 Japanese control alleles. Functional assays revealed that homozygous mutant channels were completely nonfunctional, whereas heterozygous M301K channels showed impaired inward rectification resulting in larger outward currents, which the authors stated was a novel mechanism predisposing to SQTS. </p><p>In an 11-year-old boy with recurrent paroxysmal atrial fibrillation and short QT interval, Deo et al. (2013) identified heterozygosity for a missense mutation in the KCNJ2 gene (E299V; 600681.0016). Functional analysis revealed that the E299V mutation abolishes inward rectification; heterozygous channels showed severely impaired inward rectification, resulting in a large outward current during the early phase of the action potential that markedly shortens its duration. </p><p><strong><em>Familial Atrial Fibrillation 9</em></strong></p><p>
|
|
In affected members of a Chinese family segregating autosomal dominant atrial fibrillation (ATFB9; 613980), Xia et al. (2005) identified heterozygosity for a mutation in the KCNJ2 gene (V93I; 600681.0014). Functional analysis revealed that the V93I mutation has a gain-of-function effect on the Kir2.1 current, in contrast to the loss of function observed with previously reported KCNJ2 mutations associated with the Andersen periodic paralysis syndrome. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation near the KCNJ2 gene and susceptibility to thyrotoxic periodic paralysis, see TTPP3 (614834).</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>16 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 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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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KCNJ2, ASP71VAL
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<br />
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SNP: rs104894575,
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ClinVar: RCV000009473, RCV000058298, RCV001851763
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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 the affected individuals of a pedigree (K4415) with Andersen syndrome (170390), Plaster et al. (2001) identified a heterozygous (dominant) mutation in the KCNJ2 gene. The A-to-T transversion at nucleotide 440 resulted in an asp71-to-val substitution in the N terminus of the KCNJ2 protein. The mutation was not found in 100 unaffected and unrelated individuals. Expression of this mutation in Xenopus oocytes revealed loss of function and a dominant-negative effect in KCNJ2 current as assayed by voltage-clamp. </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 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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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KCNJ2, ARG218TRP
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<br />
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SNP: rs104894578,
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ClinVar: RCV000009474, RCV000058326, RCV000170982, RCV000684775, RCV004018605
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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 the affected individuals of 4 different pedigrees (K2679, K6515, K2681, and K2401) with Andersen syndrome (170390), Plaster et al. (2001) identified a heterozygous (dominant) mutation in the KCNJ2 gene. The C-to-T transition at nucleotide 880 resulted in an arg218-to-trp (R218W) substitution within the C-terminal interaction domain of the KCNJ2 protein. The mutation occurred de novo in 3 pedigrees, and it was not found in 100 unaffected and unrelated individuals. Expression of this mutation in Xenopus oocytes revealed loss of function and a dominant-negative effect in KCNJ2 current as assayed by voltage-clamp. </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 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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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KCNJ2, GLY300VAL
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<br />
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SNP: rs104894579,
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ClinVar: RCV000009475, RCV000058332, RCV000170987, RCV002512943, RCV004629139
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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 the affected individuals of 2 different pedigrees (K3677 and K3387) with Andersen syndrome (170390), Plaster et al. (2001) identified a heterozygous (dominant) mutation in the KCNJ2 gene. The G-to-T transversion at nucleotide 1127 resulted in a gly300-to-val substitution. This mutation was not found in 100 unaffected and unrelated individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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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KCNJ2, 12-BP DEL, NT513
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<br />
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SNP: rs2144376746,
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ClinVar: RCV000009476
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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 affected individual of a pedigree (K2281) with Andersen syndrome (170390), Plaster et al. (2001) identified a heterozygous (dominant) in-frame deletion of 12 nucleotides in the KCNJ2 gene, resulting in the deletion of amino acids 95 to 98 in the M1 transmembrane segment. This mutation was not found in 100 unaffected and unrelated individuals. </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>.0005 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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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KCNJ2, 6-BP DEL, NT1167
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<br />
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SNP: rs2074390325,
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ClinVar: RCV001260872, RCV001379609
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In an affected individual of a pedigree (K5768) with Andersen syndrome (170390), Plaster et al. (2001) identified a heterozygous (dominant) in-frame deletion of 6 nucleotides in the KCNJ2 gene, resulting in the deletion of amino acids 314 to 315. This mutation occurred de novo in this family and was not found in 100 unaffected and unrelated individuals. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ2, ARG67TRP
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|
<br />
|
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|
|
SNP: rs104894580,
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|
|
gnomAD: rs104894580,
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|
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ClinVar: RCV000009478, RCV000058294, RCV000170971, RCV000763415, RCV000814909, RCV001000954, RCV002415408
|
|
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>See Andersen cardiodysrhythmic periodic paralysis (170390). Andelfinger et al. (2002) identified a heterozygous missense mutation (arg67 to trp; R67W) in the KCNJ2 gene in 41 members of a kindred with ventricular arrhythmias (13 of 16 female members, 81%) and periodic paralysis (10 of 25 male members, 40%) segregating as autosomal dominant traits with sex-specific variable expressivity. Some mutation carriers exhibited dysmorphic features, including hypertelorism, small mandible, syndactyly, clinodactyly, cleft palate, and scoliosis, which, together with cardiodysrhythmic periodic paralysis, constitute Andersen syndrome (170390). However, no individual exhibited all manifestations of Andersen syndrome, and this diagnosis was not considered in the proband until other family members were examined. Other features seen in this kindred included unilateral dysplastic kidney and cardiovascular malformation (i.e., bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis), which had not previously been associated with Andersen syndrome. Nonspecific electrocardiographic abnormalities were identified in some individuals, but none had a prolonged QT interval. </p><p>Andelfinger et al. (2002) stated that sex specificity of cardiac arrhythmias and periodic paralysis had not previously been described in Andersen syndrome. However, there had been an increasing recognition of specific electrocardiographic and electrophysiologic differences--for example, resting heart rate and corrected QT intervals--between males and females, but the precise way in which sex and gonadal steroids contribute to these differences was not known (Pham and Rosen, 2002; Wolbrette et al., 2002). Female subjects with the R67W mutation typically noted onset of ventricular arrhythmia after age 10 years. An increased incidence is usually reported during pregnancy, but female subjects with R67W reported reduced ventricular arrhythmias during pregnancy and after age 55 years, coinciding with menopause. </p>
|
|
</span>
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|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ2, PRO186LEU
|
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|
|
|
<br />
|
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|
|
SNP: rs104894581,
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|
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|
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|
|
ClinVar: RCV000009479, RCV000058319
|
|
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|
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</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a kindred with Andersen syndrome (170390), Tristani-Firouzi et al. (2002) identified a C-to-T transition at nucleotide 785 of the KCNJ2 gene, which resulted in a pro186-to-leu (P186L) amino acid substitution. This mutation alters an amino acid of a PKKR motif (amino acids 186-189), a C-terminal motif implicated in binding the signaling phospholipid PIP2. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ2, VAL302MET
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs104894582,
|
|
|
|
|
|
|
|
ClinVar: RCV000009480, RCV000058333
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a kindred with Andersen syndrome (170390), Tristani-Firouzi et al. (2002) found a G-to-A transition at nucleotide 1132 of the KCNJ2 gene, resulting in a val302-to-met (V302M) amino acid change. This mutation lies in a C-terminal region that may be responsible for channel subunit assembly. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ2, ASN216HIS
|
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|
|
|
<br />
|
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|
|
SNP: rs104894583,
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|
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|
|
ClinVar: RCV000009481, RCV000058324
|
|
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a kindred with Andersen syndrome (170390), Tristani-Firouzi et al. (2002) identified an A-to-C transversion at nucleotide 874 of the KCNJ2 gene, which resulted in an asn261-to-his (N216H) amino acid change. This mutation lies within a C-terminal region (amino acids 207-246) thought to be involved in PIP2 interactions. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SHORT QT SYNDROME 3</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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KCNJ2, ASP172ASN
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<br />
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|
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SNP: rs104894584,
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|
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ClinVar: RCV000009482, RCV000058318, RCV001384722
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old girl and her father with short QT syndrome-3 (SQT3; 609622), Priori et al. (2005) identified a 514G-A transition in the KCNJ2 gene, resulting in an asp172-to-asn (D172N) substitution. The mutation was not found in unaffected family members. Functional studies revealed a significant increase in the outward component of the I-V relation of I(K1). </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Using 2D ventricular cell and 3D tissue models, Adeniran et al. (2012) studied the effects of the Kir2.1 D172N mutation. They found that the D172N mutation abbreviates the action potential duration (APD) at 90% of repolarization (APD90) and steepens the restitution of APD and effective refractory period (ERP) curves, thus increasing susceptibility to arrhythmia; shortens the QT interval and alters the morphology of T-waves, which were tall, peaked, and asymmetric, similar to those of the Priori et al. (2005) proband; augments the transmural dispersion of APD90 across the ventricular wall, which leads to the increase, at some localized regions, of the temporal vulnerability of the tissue to the genesis of unidirectional conduction by premature excitation; reduces the minimal substrate size of tissue required to initiate and maintain reentry; and stabilizes and accelerates reentrant excitation waves. The authors concluded that the D172N mutant results in increased transmural APD dispersion that increases tissue vulnerability to the genesis of reentry with premature exitation, and also shortens the ventricular tissue ERP, which facilitates the maintenance of reentry once it has been initiated. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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KCNJ2, THR75ARG
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<br />
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SNP: rs104894585,
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ClinVar: RCV000009483, RCV000058301, RCV001851764
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a family with Andersen syndrome (170390), Lu et al. (2006) identified heterozygosity for a 224C-G transversion, resulting in a thr75-to-arg (T75R) substitution at a highly conserved codon in the cytoplasmic N-terminal portion of Kir2.1. The mutation was not found in 2 unaffected family members or in 100 unrelated controls. Although the mutant protein was able to coassemble and traffic to the cell membrane in mouse atrial cardiomyocytes, voltage clamp analysis in Xenopus oocytes revealed that the mutant channel was nonfunctional; upon coexpression of mutant and wildtype cRNA in Xenopus oocytes, the K(+) current was completely lost, demonstrating the strong dominant-negative effect of the T75R mutant. Transgenic T75R mice had bidirectional ventricular tachycardia after induction and longer QT intervals. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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KCNJ2, CYS54PHE
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<br />
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SNP: rs199473650,
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ClinVar: RCV000023027, RCV000058293
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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 19-year-old man with periodic paralysis and cardiac dysrhythmias (170390), triggered by use of corticosteroids on at least 2 occasions, Bendahhou et al. (2007) identified heterozygosity for a 489G-T transversion in the KCNJ2 gene, resulting in a cys54-to-phe (C54F) substitution at a conserved residue in the N terminus. Functional expression in mammalian cells revealed loss of function when the mutant was expressed alone and a dominant-negative effect when expressed with wildtype channels; however, channel trafficking and assembly were not affected. The proband's unaffected brother and father also carried the mutation. Aside from a small chin in the proband, there were no dysmorphic features in this family. </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>.0013 ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS</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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KCNJ2, THR305PRO
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<br />
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SNP: rs199473387,
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ClinVar: RCV000023028, RCV000058335
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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 23-year-old woman with periodic paralysis and cardiac dysrhythmias that began in childhood (170390), Bendahhou et al. (2007) identified heterozygosity for a 1141A-C transversion in the KCNJ2 gene, resulting in a thr305-to-pro (T305P) substitution at a conserved residue in the C terminus. Functional expression in mammalian cells revealed loss of function when the mutant was expressed alone and a dominant-negative effect when expressed with wildtype channels; however, channel trafficking and assembly were not affected. There were no dysmorphic features in the proband. Her mother, maternal aunt, and maternal grandmother had a history of cardiac dysrhythmias, and the grandmother had a pacemaker. </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>.0014 ATRIAL FIBRILLATION, FAMILIAL, 9</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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KCNJ2, VAL93ILE
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<br />
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SNP: rs147750704,
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gnomAD: rs147750704,
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ClinVar: RCV000023029, RCV000148540, RCV000170978, RCV000544361, RCV001127504, RCV001127505, RCV002433466, RCV003318334
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a Chinese family with atrial fibrillation (ATFB9; 613980), Xia et al. (2005) identified heterozygosity for a 227G-A transition in the KCNJ2 gene, resulting in a val93-to-ile (V93I) substitution at a highly conserved residue. The mutation was not found in 420 controls. Patch-clamp studies in COS-7 and HEK293 cells demonstrated that the V93I mutation has a gain-of-function effect on Kir2.1 channels. </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>.0015 SHORT QT SYNDROME 3</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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KCNJ2, MET301LYS
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<br />
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ClinVar: RCV003481514
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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 8-year-old Japanese girl with a markedly short QT interval (SQT3; 609622), Hattori et al. (2012) identified heterozygosity for a c.902T-A transversion in the KCNJ2 gene, resulting in a met301-to-lys (M301K) substitution at a highly conserved residue within a pore-facing loop region in the C-terminal cytoplasmic domain. Family DNA was unavailable for study, but the variant was not found in 400 Japanese control alleles. Functional characterization of mutant channels in HEK293 cells showed that homozygous mutant channels were entirely nonfunctional, whereas heterozygous channels had very weak inward rectification, which resulted in significantly larger outward current densities at potentials between -30 and +100 mV. Studies using transiently transfected neonatal rat ventricular myocytes demonstrated that significant increases in outward currents within the voltage range of action potentials (APs) shortened the AP duration by accelerating membrane repolarization. Whole-cell patch-clamp recordings revealed the importance of a neutral amino acid residue like methionine at position 301 for generating Kir2.1 inward rectification: substituting a different neutral (alanine) or a positively charged (arginine) residue at M301 resulted in function similar to wildtype with the former, and attenuated inward rectification with the latter, similar to that seen with the M301K mutant. </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>.0016 SHORT QT SYNDROME 3</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ2, GLU299VAL
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<br />
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|
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SNP: rs786205817,
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|
|
ClinVar: RCV000170986, RCV003482239
|
|
|
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|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old boy with recurrent paroxysmal atrial fibrillation and short QT interval (SQT3; 609622), Deo et al. (2013) identified heterozygosity for a de novo c.896A-T transversion in the KCNJ2 gene, resulting in a glu299-to-val (E299V) substitution at a highly conserved residue within the Kir2.1 cytoplasmic terminal. The mutation was not found in his parents or in 400 control individuals. Functional analysis in HEK293 cells showed a significant reduction of the inward current with the heterozygous E299V mutant channel compared to wildtype, with major impairment at more positive voltages. Action potential clamp recordings confirmed severely impaired inward rectification with the E299V mutant, resulting in a large outward current during the early phase of the action potential that dramatically shortens the action potential duration. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
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<div>
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<p />
|
|
</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">
|
|
Adeniran, I., El Harchi, A., Hancox, J. C., Zhang, H.
|
|
<strong>Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling.</strong>
|
|
Cardiovasc. Res. 94: 66-76, 2012.
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[PubMed: 22308236]
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[Full Text: https://doi.org/10.1093/cvr/cvs082]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Andelfinger, G., Tapper, A. R., Welch, R. C., Vanoye, C. G., George, A. L., Jr., Benson, D. W.
|
|
<strong>KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes.</strong>
|
|
Am. J. Hum. Genet. 71: 663-668, 2002.
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[PubMed: 12148092]
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[Full Text: https://doi.org/10.1086/342360]
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</p>
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<li>
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<p class="mim-text-font">
|
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Bendahhou, S., Fournier, E., Gallet, S., Menard, D., Larroque, M.-M., Barhanin, J.
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<strong>Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred.</strong>
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Hum. Molec. Genet. 16: 900-906, 2007.
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[PubMed: 17324964]
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[Full Text: https://doi.org/10.1093/hmg/ddm034]
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</p>
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<li>
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<p class="mim-text-font">
|
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Choi, B.-O., Kim, J., Suh, B. C., Yu, J. S., Sunwoo, I. N., Kim, S. J., Kim, G. H., Chung, K. W.
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<strong>Mutations of KCNJ2 gene associated with Andersen-Tawil syndrome in Korean families.</strong>
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J. Hum. Genet. 52: 280-283, 2007.
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[PubMed: 17211524]
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[Full Text: https://doi.org/10.1007/s10038-006-0100-7]
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</p>
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<li>
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<p class="mim-text-font">
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Davies, N. P., Imbrici, P., Fialho, D., Herd, C., Bilsland, L. G., Weber, A., Mueller, R., Hilton-Jones, D., Ealing, J., Boothman, B. R., Giunti, P., Parsons, L. M., Thomas, M., Manzur, A. Y., Jurkat-Rott, K., Lehmann-Horn, F., Chinnery, P. F., Rose, M., Kullmann, D. M., Hanna, M. G.
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<strong>Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation.</strong>
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Neurology 65: 1083-1089, 2005.
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[PubMed: 16217063]
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[Full Text: https://doi.org/10.1212/01.wnl.0000178888.03767.74]
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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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Deo, M., Ruan, Y., Pandit, S. V., Shah, K., Berenfeld, O., Blaufox, A., Cerrone, M., Noujaim, S. F., Denegri, M., Jalife, J., Priori, S. G.
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<strong>KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.</strong>
|
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Proc. Nat. Acad. Sci. 110: 4291-4296, 2013.
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[PubMed: 23440193]
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[Full Text: https://doi.org/10.1073/pnas.1218154110]
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<li>
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<p class="mim-text-font">
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Derst, C., Karschin, C., Wischmeyer, E., Hirsch, J. R., Preisig-Muller, R., Rajan, S., Engel, H., Grzeschik, K.-H., Daut, J., Karschin, A.
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<strong>Genetic and functional linkage of Kir5.1 and Kir2.1 channel subunits.</strong>
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FEBS Lett. 491: 305-311, 2001.
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[PubMed: 11240146]
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[Full Text: https://doi.org/10.1016/s0014-5793(01)02202-5]
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<p class="mim-text-font">
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Donaldson, M. R., Jensen, J. L., Tristani-Firouzi, M., Tawil, R., Bendahhou, S., Suarez, W. A., Cobo, A. M., Poza, J. J., Behr, E., Wagstaff, J., Szepetowski, P., Pereira, S., Mozaffar, T., Escolar, D. M., Fu, Y.-H., Ptacek, L. J.
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<strong>PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.</strong>
|
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Neurology 60: 1811-1816, 2003.
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[PubMed: 12796536]
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[Full Text: https://doi.org/10.1212/01.wnl.0000072261.14060.47]
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<li>
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<p class="mim-text-font">
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Doyle, D. A., Morais Cabral, J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L., Chait, B. T., MacKinnon, R.
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<strong>The structure of the potassium channel: molecular basis of K+ conduction and selectivity.</strong>
|
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Science 280: 69-77, 1998.
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[PubMed: 9525859]
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[Full Text: https://doi.org/10.1126/science.280.5360.69]
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<li>
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<p class="mim-text-font">
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Epshtein, Y., Chopra, A. P., Rosenhouse-Dantsker, A., Kowalsky, G. B., Logothetis, D. E., Levitan, I.
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<strong>Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol.</strong>
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Proc. Nat. Acad. Sci. 106: 8055-8060, 2009.
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[PubMed: 19416905]
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[Full Text: https://doi.org/10.1073/pnas.0809847106]
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<li>
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<p class="mim-text-font">
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Hattori, T., Makiyama, T., Akao, M., Ehara, E., Ohno, S., Iguchi, M., Nishio, Y., Sasaki, K., Itoh, H., Yokode, M., Kita, T., Horie, M., Kimura, T.
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<strong>A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.</strong>
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Cardiovasc. Res. 93: 666-673, 2012.
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[PubMed: 22155372]
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[Full Text: https://doi.org/10.1093/cvr/cvr329]
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</li>
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<li>
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<p class="mim-text-font">
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Kubo, Y., Baldwin, T. J., Jan, Y. N., Jan, L. Y.
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<strong>Primary structure and functional expression of a mouse inward rectifier potassium channel.</strong>
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Nature 362: 127-133, 1993.
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[PubMed: 7680768]
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[Full Text: https://doi.org/10.1038/362127a0]
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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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|
Lopes, C. M. B., Zhang, H., Rohacs, T., Jin, T., Yang, J., Logothetis, D. E.
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<strong>Alterations in conserved Kir channel-PIP(2) interactions underlie channelopathies.</strong>
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Neuron 34: 933-944, 2002.
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[PubMed: 12086641]
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[Full Text: https://doi.org/10.1016/s0896-6273(02)00725-0]
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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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|
Lu, C.-W., Lin, J.-H., Rajawat, Y. S., Jerng, H., Rami, T. G., Sanchez, X., DeFreitas, G., Carabello, B., DeMayo, F., Kearney, D. L., Miller, G., Li, H., Pfaffinger, P. J., Bowles, N. E., Khoury, D. S., Towbin, J. A.
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<strong>Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome.</strong>
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J. Med. Genet. 43: 653-659, 2006.
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[PubMed: 16571646]
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[Full Text: https://doi.org/10.1136/jmg.2006.040816]
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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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Lu, Z., Klem, A. M., Ramu, Y.
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<strong>Ion conduction pore is conserved among potassium channels.</strong>
|
|
Nature 413: 809-813, 2001.
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|
|
|
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[PubMed: 11677598]
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|
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|
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[Full Text: https://doi.org/10.1038/35101535]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Luo, X., Pan, Z., Shan, H., Xiao, J., Sun, X., Wang, N., Lin, H., Xiao, L., Maguy, A., Qi, X.-Y., Li, Y., Gao, X., and 11 others.
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<strong>MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation.</strong>
|
|
J. Clin. Invest. 123: 1939-1951, 2013.
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[PubMed: 23543060]
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[Full Text: https://doi.org/10.1172/JCI62185]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Miake, J., Marban, E., Nuss, H. B.
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<strong>Biological pacemaker created by gene transfer.</strong>
|
|
Nature 419: 132-133, 2002.
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|
[PubMed: 12226654]
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|
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|
|
[Full Text: https://doi.org/10.1038/419132b]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Pham, T. V., Rosen, M. R.
|
|
<strong>Sex, hormones, and repolarization.</strong>
|
|
Cardiovasc. Res. 53: 740-751, 2002.
|
|
|
|
|
|
[PubMed: 11861044]
|
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|
|
[Full Text: https://doi.org/10.1016/s0008-6363(01)00429-1]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., and 10 others.
|
|
<strong>Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.</strong>
|
|
Cell 105: 511-519, 2001.
|
|
|
|
|
|
[PubMed: 11371347]
|
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|
|
[Full Text: https://doi.org/10.1016/s0092-8674(01)00342-7]
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</p>
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</li>
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<li>
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Priori, S. G., Pandit, S. V., Rivolta, I., Berenfeld, O., Ronchetti, E., Dhamoon, A., Napolitano, C., Anumonwo, J., Raffaele di Barletta, M., Gudapakkam, S., Bosi, G., Stramba-Badiale, M., Jalife, J.
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Raab-Graham, K., Radeke, C. M., Vandenberg, C. A.
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Tristani-Firouzi, M., Jensen, J. L., Donaldson, M. R., Sansone, V., Meola, G., Hahn, A., Bendahhou, S., Kwiecinski, H., Fidzianska, A., Plaster, N., Fu, Y.-H., Ptacek, L. J., Tawil, R.
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Wolbrette, D., Naccarelli, G., Curtis, A., Lehmann, M., Kadish, A.
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<strong>Gender differences in arrhythmias.</strong>
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Xia, M., Jin, Q., Bendahhou, S., He, Y., Larroque, M.-M., Chen, Y., Zhou, Q., Yang, Y., Liu, Y., Liu, B., Zhu, Q., Zhou, Y., and 12 others.
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<strong>A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.</strong>
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Marla J. F. O'Neill - updated : 01/02/2024<br>Patricia A. Hartz - updated : 03/09/2016<br>Marla J. F. O'Neill - updated : 5/17/2011<br>Marla J. F. O'Neill - updated : 1/20/2011<br>Patricia A. Hartz - updated : 8/20/2010<br>Patricia A. Hartz - updated : 3/12/2008<br>Marla J. F. O'Neill - updated : 5/29/2007<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Marla J. F. O'Neill - updated : 8/31/2006<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Cassandra L. Kniffin - updated : 8/11/2003<br>Dawn Watkins-Chow - updated : 12/18/2002<br>Dawn Watkins-Chow - updated : 11/14/2002<br>Ada Hamosh - updated : 9/30/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 6/17/2002<br>Ada Hamosh - updated : 10/23/2001<br>Stylianos E. Antonarakis - updated : 6/4/2001
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