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Entry
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- *152427 - POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 2; KCNH2
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- OMIM
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<p>
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<span class="h4">*152427</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</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/152427">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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div 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=ENSG00000055118;t=ENST00000262186" 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=3757" 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=152427" 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=ENSG00000055118;t=ENST00000262186" 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_000238,NM_001204798,NM_001406753,NM_001406755,NM_001406756,NM_001406757,NM_172056,NM_172057,NR_176254,NR_176255,XM_011516185,XM_017012195,XM_017012196,XM_047420348,XM_047420349" 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_000238" 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=152427" 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=01069&isoform_id=01069_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/KCNH2" 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/487738,3452413,3549259,4156239,4557729,7531135,11933152,17225916,24210416,26051271,26051273,30583511,34783890,37499007,37499009,37499011,37499013,37499015,37499017,37499019,37499021,37499023,37499025,37499027,37499029,37499031,38635441,41474663,41474664,45945867,51105907,51105908,51105909,68226235,68226237,71057283,71057285,71739466,71739468,103488986,118341648,119574456,119574457,119574458,119574459,119574460,146048409,159786194,225355235,237862038,253326728,325651834,342840031,404056074,767947743,1034655561,1034655564,2217367063,2217367068,2241236925,2241236934,2241237025,2241237056,2462614287,2462614289,2462614291,2462614293,2462614295" 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/Q12809" 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=3757" 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=ENSG00000055118;t=ENST00000262186" 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=KCNH2" 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=KCNH2" 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+3757" 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/KCNH2" 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:3757" 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/3757" 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=chr7&hgg_gene=ENST00000262186.10&hgg_start=150944961&hgg_end=150978321&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6251" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6251" 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/kcnh2" 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=152427[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</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=152427[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/KCNH2/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/ENSG00000055118" 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=KCNH2" 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=KCNH2" 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=KCNH2" 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=KCNH2" title="Zhejiang University-Adinovo Center KCNH2 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><div style="margin-left: 0.5em;"><a href="http://www.ssi.dk/graphics/html/lqtsdb/lqtsdb.htm" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Long QT Syndrome Database</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=KCNH2&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/PA212" 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:6251" 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/FBgn0003353.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:1341722" 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/KCNH2#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:1341722" 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/3757/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://omia.org/OMIA002441/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3757" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006830;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070912-699" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:152427" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></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://reactome.org/content/query?q=KCNH2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<div>
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<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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152427
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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, VOLTAGE-GATED, SUBFAMILY H, MEMBER 2; KCNH2
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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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HUMAN ETHER-A-GO-GO-RELATED GENE; HERG<br />
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ETHER-A-GO-GO-RELATED GENE, HUMAN<br />
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ERG1<br />
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KV11.1
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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=KCNH2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KCNH2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/7/821?start=-3&limit=10&highlight=821">7q36.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:150944961-150978321&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'})">7:150,944,961-150,978,321</a> </span>
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</em>
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</strong>
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>KCNH2 encodes the pore-forming subunit of a rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential (<a href="#8" class="mim-tip-reference" title="Gianulis, E. C., Trudeau, M. C. <strong>Rescue of aberrant gating by a genetically encoded PAS (Per-Arnt-Sim) domain in several long QT syndrome mutant human ether-a-go-go-related gene potassium channels.</strong> J. Biol. Chem. 286: 22160-22169, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21536673[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/10.1074/jbc.M110.205948" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536673">Gianulis and Trudeau, 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536673" 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="#44" class="mim-tip-reference" title="Warmke, J. W., Ganetzky, B. <strong>A family of potassium channel genes related to eag in Drosophila and mammals.</strong> Proc. Nat. Acad. Sci. 91: 3438-3442, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8159766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8159766</a>] [<a href="https://doi.org/10.1073/pnas.91.8.3438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8159766">Warmke and Ganetzky (1994)</a> identified a novel human cDNA from a hippocampal cDNA library by homology to the Drosophila 'ether-a-go-go' (eag) gene, which encodes a Ca(2+)-modulated potassium channel. The authors called the cDNA HERG (human ether-a-go-go-related gene). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8159766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Huffaker, S. J., Chen, J., Nicodemus, K. K., Sambataro, F., Yang, F., Mattay, V., Lipska, B. K., Hyde, T. M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., and 13 others. <strong>A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.</strong> Nature Med. 15: 509-518, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.1962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412172">Huffaker et al. (2009)</a> identified a brain-specific isoform of KCNH2, which they referred to as KCNH2-3.1. The new isoform originates upstream of exon 3 of the known isoform KCNH2-1A and contains all of the downstream exons of the full-length gene through exon 15. In silico prediction of the longest open reading frame of KCNH2-3.1 suggested that the majority of the 5-prime extension of exon 3 is untranslated, and that the first methionine is in-frame with the conserved portion of KCNH2-1A. Thus, KCNH2-3.1 was predicted to be missing the first 102 amino acids of KCNH2-1A, replacing them with 6 unique amino acids. Western blot analysis of human hippocampus and frontal cortex cells confirmed the predicted difference in protein size. The KCNH2-3.1 isoform was preferentially expressed in human brain. It was not detected in mouse brain but was abundant in rhesus monkey brain, suggesting that it is primate-specific. In various human brain tissues, KCNH2-3.1 transcript levels were markedly increased prenatally relative to adult levels, but appeared to decrease and stabilize shortly after birth. In contrast, KCNH2-1A expression increased throughout prenatal development until reaching a maximum level that was sustained throughout postnatal life. The findings suggested a specific role for KCNH2-3.1 during the early stages of human brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Gianulis, E. C., Trudeau, M. C. <strong>Rescue of aberrant gating by a genetically encoded PAS (Per-Arnt-Sim) domain in several long QT syndrome mutant human ether-a-go-go-related gene potassium channels.</strong> J. Biol. Chem. 286: 22160-22169, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21536673[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/10.1074/jbc.M110.205948" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536673">Gianulis and Trudeau (2011)</a> noted that full-length KCNH2 includes an N-terminal Per (see <a href="/entry/602260">602260</a>)-Arnt (<a href="/entry/126110">126110</a>)-Sim (see <a href="/entry/603128">603128</a>) (PAS) domain that regulates channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Itoh, T., Tanaka, T., Nagai, R., Kamiya, T., Sawayama, T., Nakayama, T., Tomoike, H., Sakurada, H., Yazaki, Y., Nakamura, Y. <strong>Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome.</strong> Hum. Genet. 102: 435-439, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600240</a>] [<a href="https://doi.org/10.1007/s004390050717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600240">Itoh et al. (1998)</a> described the genomic organization of HERG. They found that the gene contains 15 exons spanning approximately 19 kb on chromosome 7q35. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600240" 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 genomic sequence analysis, <a href="#37" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Vincent, G. M., Lehmann, M. H., Keating, M. T. <strong>Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.</strong> Genomics 51: 86-97, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9693036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9693036</a>] [<a href="https://doi.org/10.1006/geno.1998.5361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9693036">Splawski et al. (1998)</a> determined that the HERG gene contains 16 exons (which included an alternative exon 1b), ranging from 100 bp to 553 bp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9693036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR analysis of a somatic cell hybrid panel, <a href="#44" class="mim-tip-reference" title="Warmke, J. W., Ganetzky, B. <strong>A family of potassium channel genes related to eag in Drosophila and mammals.</strong> Proc. Nat. Acad. Sci. 91: 3438-3442, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8159766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8159766</a>] [<a href="https://doi.org/10.1073/pnas.91.8.3438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8159766">Warmke and Ganetzky (1994)</a> localized the KCNH2 gene to human chromosome 7. <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> mapped the KCNH2 gene to chromosome 7q35-q36 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7889573+8159766" 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="#32" class="mim-tip-reference" title="Sanguinetti, M. C., Jiang, C., Curran, M. E., Keating, M. T. <strong>A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I(Kr) potassium channel.</strong> Cell 81: 299-307, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7736582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7736582</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90340-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7736582">Sanguinetti et al. (1995)</a> expressed the HERG gene in Xenopus laevis oocytes and studied the potassium channel's biophysical properties and its sensitivity to various pharmacological agents. Their data indicated that HERG proteins form I(Kr) channels, but that another subunit may be required for certain drug sensitivities. Since block of I(Kr) is a known mechanism for drug-induced cardiac arrhythmias, their findings provided a mechanistic link between certain types of inherited and acquired long QT (LQT) syndrome. Acquired long QT syndrome occurs following treatment with certain medications and in association with reduced serum potassium levels (hypokalemia). Both acquired and inherited LQT are associated with torsade de pointes and polymorphic ventricular tachycardia resulting from abnormal cardiac depolarization (as detected by QT prolongation on the electrocardiogram). LQT is also characterized by sinusoidal twisting of the QRS axis around the isoelectric line. Torsade de pointes can degenerate into ventricular fibrillation, which can lead to sudden death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7736582" 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="#42" class="mim-tip-reference" title="Trudeau, M. C., Warmke, J. W., Ganetzky, B., Robertson, G. A. <strong>HERG, a human inward rectifier in the voltage-gated potassium channel family.</strong> Science 269: 92-95, 1995. Note: Erratum: Science 272: 1087 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604285</a>] [<a href="https://doi.org/10.1126/science.7604285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604285">Trudeau et al. (1995)</a> likewise demonstrated that HERG encodes an inwardly rectifying potassium channel. Inward rectifiers are a large class of potassium channels that preferentially conduct inward potassium currents at voltages negative to the potassium equilibrium potential. In the heart, these channels also have small outward conductances that regulate the resting potential and contribute to the terminal phase of repolarization. At positive voltages, these channels close and thus help maintain the level of the resting potential. HERG channels show gating properties consistent with many of the outwardly rectifying potassium channels, but they also have an inactivation mechanism that attenuates efflux during depolarization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7604285" 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>The HERG potassium channel is unusual in that it seems to have the architectural plan of the depolarization-activated K+ channel family (6 putative transmembrane segments), yet it exhibits rectification like that of the inward-rectifying K+ channels, a family with different molecular structure (2 transmembrane segments). <a href="#35" class="mim-tip-reference" title="Smith, P. L., Baukrowitz, T., Yellen, G. <strong>The inward rectification mechanism of the HERG cardiac potassium channel.</strong> Nature 379: 833-835, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8587608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8587608</a>] [<a href="https://doi.org/10.1038/379833a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8587608">Smith et al. (1996)</a> studied HERG channels expressed in mammalian cells and found that this inward rectification arises from a rapid and voltage-dependent inactivation process that reduces conductance at positive voltages. The inactivation gating mechanism resembles that of C-type inactivation, often considered to be the 'slow inactivation' mechanism of other K+ channels. <a href="#35" class="mim-tip-reference" title="Smith, P. L., Baukrowitz, T., Yellen, G. <strong>The inward rectification mechanism of the HERG cardiac potassium channel.</strong> Nature 379: 833-835, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8587608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8587608</a>] [<a href="https://doi.org/10.1038/379833a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8587608">Smith et al. (1996)</a> noted that the characteristics of this gating suggested a specific role for this channel in the normal suppression of arrhythmias. They also commented that the role for HERG in suppressing extra beats might help explain the increased incidence of cardiac sudden death in patients that lack HERG currents, either because they carry a genetic defect (familial long QT syndrome type 2; LQT2; <a href="/entry/613688">613688</a>) or because they are being treated with class III antiarrhythmics that block HERG channels. <a href="#25" class="mim-tip-reference" title="Miller, C. <strong>The inconstancy of the human heart.</strong> Nature 379: 767-768, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8587597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8587597</a>] [<a href="https://doi.org/10.1038/379767a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8587597">Miller (1996)</a> commented on the discovery and its relation to heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8587608+8587597" 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="#23" class="mim-tip-reference" title="Li, X., Xu, J., Li, M. <strong>The human delta-1261 mutation of the HERG potassium channel results in a truncated protein that contains a subunit interaction domain and decreases the channel expression.</strong> J. Biol. Chem. 272: 705-708, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8995352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8995352</a>] [<a href="https://doi.org/10.1074/jbc.272.2.705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8995352">Li et al. (1997)</a> identified a subunit interaction domain, termed the NAB domain, in the hydrophilic cytoplasmic N terminus of HERG. This domain is responsible for the oligomerization of the protein into functional tetramers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8995352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ficker, E., Dennis, A. T., Wang, L., Brown, A. M. <strong>Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel hERG.</strong> Circ. Res. 92: e87-e100, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12775586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12775586</a>] [<a href="https://doi.org/10.1161/01.RES.0000079028.31393.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12775586">Ficker et al. (2003)</a> demonstrated that the cytosolic chaperones HSP70 (<a href="/entry/140550">140550</a>) and HSP90 (<a href="/entry/140571">140571</a>) interact directly with the core-glycosylated form of wildtype HERG gene product present in the ER, but not the fully glycosylated, cell surface form. Trafficking-deficient mutants remained tightly associated with HSP70 and HSP90 in the ER, whereas a nonfunctional but trafficking HERG was released from the chaperones during maturation, comparable to the wildtype. <a href="#6" class="mim-tip-reference" title="Ficker, E., Dennis, A. T., Wang, L., Brown, A. M. <strong>Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel hERG.</strong> Circ. Res. 92: e87-e100, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12775586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12775586</a>] [<a href="https://doi.org/10.1161/01.RES.0000079028.31393.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12775586">Ficker et al. (2003)</a> concluded that HSP90 and HSP70 are crucial for the maturation of wildtype HERG as well as the retention of trafficking-deficient LQT2 mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12775586" 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>Electrophysiologic studies in cultured cells by <a href="#13" class="mim-tip-reference" title="Huffaker, S. J., Chen, J., Nicodemus, K. K., Sambataro, F., Yang, F., Mattay, V., Lipska, B. K., Hyde, T. M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., and 13 others. <strong>A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.</strong> Nature Med. 15: 509-518, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.1962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412172">Huffaker et al. (2009)</a> showed that KCNH2-3.1 mediated an inward rectified K(+) current with a high-frequency nonadapting firing pattern and markedly faster deactivation kinetics compared to KCNH2-1A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using patch-clamp recordings of transfected HEK293 cells, <a href="#8" class="mim-tip-reference" title="Gianulis, E. C., Trudeau, M. C. <strong>Rescue of aberrant gating by a genetically encoded PAS (Per-Arnt-Sim) domain in several long QT syndrome mutant human ether-a-go-go-related gene potassium channels.</strong> J. Biol. Chem. 286: 22160-22169, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21536673[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/10.1074/jbc.M110.205948" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536673">Gianulis and Trudeau (2011)</a> showed that LQT2-associated amino acid substitutions on 1 face of the PAS domain of HERG altered channel gating. These substitutions accelerated channel deactivation kinetics, caused a positive rightward shift in the steady-state inactivation curve, and increased steady-state channel availability. Coexpression of the isolated, fluorescence-tagged PAS domain rescued the gating defect, presumably by supplanting the mutated PAS domain. Other substitutions within the PAS domain did not alter channel gating or resulted in no measurable currents. <a href="#8" class="mim-tip-reference" title="Gianulis, E. C., Trudeau, M. C. <strong>Rescue of aberrant gating by a genetically encoded PAS (Per-Arnt-Sim) domain in several long QT syndrome mutant human ether-a-go-go-related gene potassium channels.</strong> J. Biol. Chem. 286: 22160-22169, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21536673[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/10.1074/jbc.M110.205948" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536673">Gianulis and Trudeau (2011)</a> concluded that the PAS domain regulates steady-state inactivation and activation properties of HERG channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Roder, K., Werdich, A. A., Li, W., Liu, M., Kim, T. Y., Organ-Darling, L. E., Moshal, K. S., Hwang, J. M., Lu, Y., Choi, B.-R., MacRae, C. A., Koren, G. <strong>RING finger protein RNF207, a novel regulator of cardiac excitation.</strong> J. Biol. Chem. 289: 33730-33740, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25281747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25281747</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25281747[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/10.1074/jbc.M114.592295" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25281747">Roder et al. (2014)</a> found that overexpression of human RNF207 (<a href="/entry/616923">616923</a>) shortened action potential duration in neonatal rabbit ventricular cardiomyocytes. In human U2OS or HEK293 cell lines or rat cardiomyoblast H9c2 cells, overexpression of RNF207 increased membrane expression of cotransfected HERG. Elevated HERG membrane expression increased HERG tail current density, but it had no effect on other channel parameters. Mutation analysis revealed that HERG stability depended upon the RING finger domain of RNF207. RNF207 interacted with the core-glycosylated form of HERG, but not with the fully glycosylated form, in perinuclear regions, suggesting that they interact in the endoplasmic reticulum or cis-Golgi. The C terminus of RNF207 also interacted with the chaperone HSP70 (see <a href="/entry/140550">140550</a>), and cotransfection of RNF207 with HSP70 had an additive effect on HERG stability. Expression of C-terminally truncated RNF207 had a dominant-negative effect on HERG stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25281747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Long QT Syndrome 2</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> showed that the KCNH2 (HERG) gene mapped to the same YAC as D7S505, a polymorphic marker tightly linked to long QT syndrome-2 (LQT2; <a href="/entry/613688">613688</a>). They found no recombination events using linkage analysis with polymorphisms within KCNH2 for linkage studies of chromosome 7-linked LQT. Using single-strand conformation polymorphism and DNA sequence analyses, <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> detected HERG mutations in 6 LQT families, including 2 intragenic deletions, 1 splice-donor mutation, and 3 missense mutations. In 1 kindred, the mutation arose de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" 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 32 Japanese families with long QT syndrome, <a href="#38" class="mim-tip-reference" title="Tanaka, T., Nagai, R., Tomoike, H., Takata, S., Yano, K., Yabuta, K., Haneda, N., Nakano, O., Shibata, A., Sawayama, T., Kasai, H., Yazaki, Y., Nakamura, Y. <strong>Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.</strong> Circulation 95: 565-567, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024139</a>] [<a href="https://doi.org/10.1161/01.cir.95.3.565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9024139">Tanaka et al. (1997)</a> found that 5 families (9 patients) segregated mutant alleles of HERG. All were missense mutations and only 1, ala561-to-val (A561V; <a href="#0001">152427.0001</a>), had previously been reported. <a href="#33" class="mim-tip-reference" title="Satler, C. A., Vesely, M. R., Duggal, P., Ginsburg, G. S., Beggs, A. H. <strong>Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome.</strong> Hum. Genet. 102: 265-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9544837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9544837</a>] [<a href="https://doi.org/10.1007/s004390050690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9544837">Satler et al. (1998)</a> described 5 HERG mutations in 6 unrelated LQT kindreds. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9024139+9544837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Itoh, T., Tanaka, T., Nagai, R., Kamiya, T., Sawayama, T., Nakayama, T., Tomoike, H., Sakurada, H., Yazaki, Y., Nakamura, Y. <strong>Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome.</strong> Hum. Genet. 102: 435-439, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600240</a>] [<a href="https://doi.org/10.1007/s004390050717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600240">Itoh et al. (1998)</a> synthesized oligonucleotide primers to cover the entire coding region of HERG and searched for mutations in 36 Japanese families with long QT syndrome. They identified 5 novel mutations, using a combination of PCR/SSCP followed by direct DNA sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600240" 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="#50" class="mim-tip-reference" title="Zhou, Z., Gong, Q., Epstein, M. L., January, C. T. <strong>HERG channel dysfunction in human long QT syndrome: intracellular transport and functional defects.</strong> J. Biol. Chem. 273: 21061-21066, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694858</a>] [<a href="https://doi.org/10.1074/jbc.273.33.21061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9694858">Zhou et al. (1998)</a> used electrophysiologic, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT2 mutations. They found that some mutations, e.g., tyr611 to his (Y611H; <a href="#0027">152427.0027</a>) and val822 to met (<a href="#0005">152427.0005</a>), caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum (ER). Other mutations, e.g., ile593 to arg (<a href="#0004">152427.0004</a>) and gly628 to ser (<a href="#0008">152427.0008</a>), were processed similarly to wildtype HERG protein, but these mutations did not produce functional channels. In contrast, the thr474-to-ile mutation expressed HERG current but with altered gating properties. These findings suggested that the loss of HERG channel function in LQT2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9694858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large collaborative study, <a href="#49" class="mim-tip-reference" title="Zareba, W., Moss, A. J., Schwartz, P. J., Vincent, G. M., Robinson, J. L., Priori, S. G., Benhorin, J., Locati, E. H., Towbin, J. A., Keating, M. T., Lehmann, M. H., Hall, W. J., International Long-QT Syndrome Registry Research Group. <strong>Influence of the genotype on the clinical course of the long-QT syndrome.</strong> New Eng. J. Med. 339: 960-965, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753711</a>] [<a href="https://doi.org/10.1056/NEJM199810013391404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9753711">Zareba et al. (1998)</a> determined the influence of genotype on phenotype of the long QT syndrome; 112 persons had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 (<a href="/entry/603830">603830</a>) locus. The frequency of cardiac events (syncope, aborted cardiac arrest, or sudden death) was highest with mutations at the LQT1 locus (63%) or the LQT2 locus (46%) than among subjects with mutations at the LQT3 locus (18%). The cumulative mortality through the age of 40 among members of 3 groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher among families with mutations at the LQT3 locus (20%) than among those with mutations at the LQT1 locus (4%) or the LQT2 locus (4%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753711" 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="#29" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Schwartz, P. J. <strong>Low penetrance in the long QT syndrome: clinical impact.</strong> Circulation 99: 529-533, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9927399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9927399</a>] [<a href="https://doi.org/10.1161/01.cir.99.4.529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9927399">Priori et al. (1999)</a> identified 9 families, each with a 'sporadic' case of LQTS, i.e., only the proband was diagnosed clinically as being affected by LQTS. Six probands were symptomatic for syncope, 2 were asymptomatic with QT prolongation found on routine examination, and 1 was asymptomatic but showed QT prolongation when examined following her brother's sudden death while swimming. Five had mutations in HERG (4 missense, 1 nonsense) and 4 had missense mutations in KCNQ1 (<a href="/entry/607542">607542</a>). Four of the mutations were de novo; in the remaining families at least 1 silent gene carrier was found, allowing estimation of penetrance at 25%. This contrasted greatly with the prevailing view that LQTS gene mutations may have penetrances of 90% or more. This study highlighted the importance of detecting such silent gene carriers since they are at risk of developing torsade de pointes if exposed to drugs that block potassium channels. Further, the authors stated, carrier status cannot be reliably excluded on clinical grounds alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9927399" 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 severely affected sisters from a large Belgian family with long QT syndrome, <a href="#3" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; <a href="/entry/607542#0009">607542.0009</a>) and a splice site mutation in the KCNH2 gene (2592+1G-A; <a href="#0019">152427.0019</a>). <a href="#3" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> stated that this was the first description of double heterozygosity in long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10086971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. <strong>Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.</strong> Circulation 102: 1178-1185, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973849</a>] [<a href="https://doi.org/10.1161/01.cir.102.10.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973849">Splawski et al. (2000)</a> screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2; SCN5A, <a href="/entry/600163">600163</a>; KCNE1, <a href="/entry/176261">176261</a>; KCNE2, <a href="/entry/603796">603796</a>) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973849" 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="#26" class="mim-tip-reference" title="Moss, A. J., Zareba, W., Kaufman, E. S., Gartman, E., Peterson, D. R., Benhorin, J., Towbin, J. A., Keating, M. T., Priori, S. G., Schwartz, P. J., Vincent, G. M., Robinson, J. L., Andrews, M. L., Feng, C., Hall, W. J., Medina, A., Zhang, L., Wang, Z. <strong>Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel.</strong> Circulation 105: 794-799, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854117</a>] [<a href="https://doi.org/10.1161/hc0702.105124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854117">Moss et al. (2002)</a> investigated the clinical features and prognostic implications of mutations involving the pore and nonpore regions of the HERG channel in LQT2. Forty-four different mutations in this gene were identified in 201 subjects, with 14 localized to the pore region (amino acid residues 550 through 650). A total of 35 individuals had mutations in the pore region and 166 in nonpore regions. Those with pore mutations had a markedly increased risk for arrhythmia-associated cardiac events (syncope, cardiac arrest, or sudden death) compared with those with nonpore mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854117" 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="#47" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al. (2002)</a> analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (<a href="/entry/607542#0031">607542.0031</a>) and 1 in KCNH2 (<a href="#0014">152427.0014</a>), not found in 228 controls, that were shown to reduce K+ currents in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" 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>Failure of cell surface expression because of defective HERG trafficking is known to cause LQT2 in some cases. Defective trafficking of membrane proteins results in a variety of other human diseases, as reviewed by <a href="#41" class="mim-tip-reference" title="Thomas, P. J., Qu, B.-H., Pedersen, P. L. <strong>Defective protein folding as a basis of human disease.</strong> Trends Biochem. Sci. 20: 456-459, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8578588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8578588</a>] [<a href="https://doi.org/10.1016/s0968-0004(00)89100-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8578588">Thomas et al. (1995)</a>. Membrane proteins are synthesized in the ER; misfolded and incompletely assembled proteins are common side products of ER protein synthesis, and a quality control mechanism recognizes such defects and results in their retention in the ER. If the defect cannot be corrected by an ER-associated chaperone, the protein is retrotranslocated to the cytosol and targeted for the degradative pathway. One ER retention signal is the amino acid triplet RXR, where 'X' can be any amino acid, although a large neutral or positively charged amino acid is preferred. <a href="#19" class="mim-tip-reference" title="Kupershmidt, S., Yang, T., Chanthaphaychith, S., Wang, Z., Towbin, J. A., Roden, D. M. <strong>Defective human ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus.</strong> J. Biol. Chem. 277: 27442-27448, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12021266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12021266</a>] [<a href="https://doi.org/10.1074/jbc.M112375200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12021266">Kupershmidt et al. (2002)</a> identified an RXR motif in the C terminus of HERG which, when exposed by mutation, resulted in reduced cell surface trafficking. They studied the effect of a trp1001-to-ter (W1001X; <a href="#0012">152427.0012</a>) mutation, resulting in deletion of the C-terminal 159 amino acids of HERG (del159), with that of removal of the C-terminal 147 amino acids (del147). The 12 amino acids present in HERG-del147 and absent in HERG-del159 included the presumed ER retention signal RGR. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8578588+12021266" 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 44 unrelated patients with LQT syndrome, <a href="#24" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., <a href="#0020">152427.0020</a> and <a href="#0022">152427.0022</a>-<a href="#0023">152427.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Dutch family with long QT syndrome in which affected members carried an A558P mutation in the KCNH2 gene in heterozygosity (<a href="#0025">152427.0025</a>), <a href="#1" class="mim-tip-reference" title="Amin, A. S., Herfst, L. J., Delisle, B. P., Klemens, C. A., Rook, M. B., Bezzina, C. R., Underkofler, H. A. S., Holzem, K. M., Ruijter, J. M., Tan, H. L., January, C. T., Wilde, A. A. M. <strong>Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.</strong> J. Clin. Invest. 118: 2552-2561, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18551196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18551196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18551196[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/JCI35337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18551196">Amin et al. (2008)</a> described fever-induced QT prolongation and demonstrated that the A558P mutation is trafficking-deficient, that it has a dominant-negative effect in coassembly with wildtype subunits, and that its current density fails to increase with increasing temperature to the same extent as wildtype channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18551196" 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 1</em></strong></p><p>
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In 2 families with short QT syndrome-1 (SQT1; <a href="/entry/609620">609620</a>), previously reported by <a href="#7" class="mim-tip-reference" title="Gaita, F., Giustetto, C., Bianchi, F., Wolpert, C., Schimpf, R., Riccardi, R., Grossi, S., Richiardi, E., Borggrefe, M. <strong>Short QT syndrome: a familial cause of sudden death.</strong> Circulation 108: 965-970, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925462</a>] [<a href="https://doi.org/10.1161/01.CIR.0000085071.28695.C4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925462">Gaita et al. (2003)</a>, <a href="#4" class="mim-tip-reference" title="Brugada, R., Hong, K., Dumaine, R., Cordeiro, J., Gaita, F., Borggrefe, M., Menendez, T. M., Brugada, J., Pollevick, G. D., Wolpert, C., Burashnikov, E., Matsuo, K., Wu, Y. S., Guerchicoff, A., Bianchi, F., Giustetto, C., Schimpf, R., Brugada, P., Antzelevitch, C. <strong>Sudden death associated with short-QT syndrome linked to mutations in HERG.</strong> Circulation 109: 30-35, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676148</a>] [<a href="https://doi.org/10.1161/01.CIR.0000109482.92774.3A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676148">Brugada et al. (2004)</a> identified 2 different missense mutations in the KCNH2 gene (<a href="#0017">152427.0017</a> and <a href="#0018">152427.0018</a>, respectively), leading to the same asn588-to-lys (N588K) substitution. The mutation was present in all affected family members and in none of the unaffected individuals. Patch-clamp experiments revealed that the mutation dramatically increases I(Kr), leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduces the affinity of the channels to I(Kr) blockers. <a href="#12" class="mim-tip-reference" title="Hong, K., Bjerregaard, P., Gussak, I., Brugada, R. <strong>Short QT syndrome and atrial fibrillation caused by mutation in KCNH2.</strong> J. Cardiovasc. Electrophysiol. 16: 394-396, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15828882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15828882</a>] [<a href="https://doi.org/10.1046/j.1540-8167.2005.40621.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15828882">Hong et al. (2005)</a> identified the N588K mutation in a third family with short QT syndrome, originally described by <a href="#11" class="mim-tip-reference" title="Gussak, I., Brugada, P., Brugada, J., Wright, R. S., Kopecky, S. L., Chaitman, B. R., Bjerregaard, P. <strong>Idiopathic short QT interval: a new clinical syndrome?</strong> Cardiology 94: 99-102, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173780</a>] [<a href="https://doi.org/10.1159/000047299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173780">Gussak et al. (2000)</a>, and concluded that codon 588 is a hotspot for this familial form of the short QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12925462+15828882+14676148+11173780" 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>Susceptibility to Schizophrenia</em></strong></p><p>
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In a metaanalysis of 5 independent studies including a total of 1,158 patients with schizophrenia (<a href="/entry/181500">181500</a>) and 1,704 controls, <a href="#13" class="mim-tip-reference" title="Huffaker, S. J., Chen, J., Nicodemus, K. K., Sambataro, F., Yang, F., Mattay, V., Lipska, B. K., Hyde, T. M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., and 13 others. <strong>A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.</strong> Nature Med. 15: 509-518, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.1962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412172">Huffaker et al. (2009)</a> found an association between the disorder and SNPs in intron 2 of the KCNH2 gene, in close proximity to the start site of the KCNH2-3.1 isoform. Control individuals with the at-risk SNPs showed lower IQ scores, decreased speed of cognitive processing, and altered memory-linked functional MRI signals, suggesting inefficient hippocampal activity, compared to controls without these SNPs. Patients with schizophrenia and those with the at-risk SNPs showed increased expression of the brain-specific isoform KCNH2-3.1 relative to KCNH2-1A compared to controls. Expression of KCNH2-1B, a minor isoform expressed within the brain, did not show significant differences between controls and patients with schizophrenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412172" 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="#45" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, 18 of whom were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see <a href="#0021">152427.0021</a>). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. <a href="#45" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15051636" 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>Reclassified Variants</em></strong></p><p>
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The I446V variant in the KCNH2 gene described by <a href="#47" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al. (2002)</a> has been reclassified; see <a href="#0014">152427.0014</a>. <a href="#47" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al. (2002)</a> analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (<a href="/entry/607542#0031">607542.0031</a>) and 1 in KCNH2 (I446V; <a href="#0014">152427.0014</a>), not found in 228 controls, that were shown to reduce K+ currents in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" 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>Through homologous recombination in mouse embryonic stem cells, <a href="#22" class="mim-tip-reference" title="Lees-Miller, J. P., Guo, J., Somers, J. R., Roach, D. E., Sheldon, R. S., Rancourt, D. E., Duff, H. J. <strong>Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia.</strong> Molec. Cell. Biol. 23: 1856-1862, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12612061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.6.1856-1862.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612061">Lees-Miller et al. (2003)</a> eliminated the ERG1 B potassium channel transcript while the ERG1 A transcript remained. Heterologous expression of ERG1 isoforms had previously indicated that the deactivation time course of ERG1 B is 10-fold more rapid than that of ERG1 A. In day 18 fetal +/+ myocytes, I(Kr) exhibited 2 time constants of deactivation, whereas in age-matched ERG1 B -/- mice the rapid component was absent. In adult ERG1 B -/- myocytes no I(Kr) was detected. Electrocardiogram intervals were similar in 6 of 21 +/+ and -/- mice; however, adult -/- mice manifested abrupt spontaneous episodes of sinus bradycardia This phenomenon was never observed in +/+ mice. Thus, ERG1 B appears to be necessary for I(Kr) expression in the surface membrane of adult myocytes. <a href="#22" class="mim-tip-reference" title="Lees-Miller, J. P., Guo, J., Somers, J. R., Roach, D. E., Sheldon, R. S., Rancourt, D. E., Duff, H. J. <strong>Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia.</strong> Molec. Cell. Biol. 23: 1856-1862, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12612061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.6.1856-1862.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612061">Lees-Miller et al. (2003)</a> concluded that knockout of ERG1 B predisposes mice to episodic sinus bradycardia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612061" 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="#30" class="mim-tip-reference" title="Rihel, J., Prober, D. A., Arvanites, A., Lam, K., Zimmerman, S., Jang, S., Haggarty, S. J., Kokel, D., Rubin, L. L., Peterson, R. T., Schier, A. F. <strong>Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation.</strong> Science 327: 348-351, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20075256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20075256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20075256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1183090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20075256">Rihel et al. (2010)</a> reported the development and application of a high-throughput quantitative screen for drugs that alter the behavior of larval zebrafish. They found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. <a href="#30" class="mim-tip-reference" title="Rihel, J., Prober, D. A., Arvanites, A., Lam, K., Zimmerman, S., Jang, S., Haggarty, S. J., Kokel, D., Rubin, L. L., Peterson, R. T., Schier, A. F. <strong>Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation.</strong> Science 327: 348-351, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20075256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20075256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20075256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1183090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20075256">Rihel et al. (2010)</a> found that ERG-blocking compounds specifically increased waking activity at night. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20075256" 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 study by <a href="#46" class="mim-tip-reference" title="Xiao, J., Luo, X., Lin, H., Zhang, Y., Lu, Y., Wang, N., Zhang, Y., Yang, B., Wang, Z. <strong>MicroRNA miR-133 represses HERG K(+) channel expression contributing to QT prolongation in diabetic hearts.</strong> J. Biol. Chem. 282: 12363-12367, 2007. Note: Retraction: J. Biol. Chem. 286: 28656 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344217</a>] [<a href="https://doi.org/10.1074/jbc.C700015200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344217">Xiao et al. (2007)</a> in rabbits, suggesting that repression of ERG by miR133 (<a href="/entry/610254">610254</a>) likely underlies differential changes of ERG protein and transcript in diabetic hearts, results in reduced I(Kr) density, and contributes to QT prolongation and associated arrhythmias, was retracted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015501 OR RCV000057941 OR RCV000181806 OR RCV000229360 OR RCV000620827 OR RCV000626630 OR RCV003492296 OR RCV004562210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015501, RCV000057941, RCV000181806, RCV000229360, RCV000620827, RCV000626630, RCV003492296, RCV004562210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015501...</a>
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<p>In affected members of kindred with long QT syndrome showing linkage to chromosome 7 (LQT2; <a href="/entry/613688">613688</a>), <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> demonstrated an abnormal SSCP conformer that cosegregated with the disease. DNA sequence analyses of the normal and aberrant conformers demonstrated a C-to-T substitution at position 1682. This mutation resulted in substitution of valine for a highly conserved alanine residue at codon 561 (A561V). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" 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 investigate mechanisms of dominant-negative behavior, <a href="#18" class="mim-tip-reference" title="Kagan, A., Yu, Z., Fishman, G. I., McDonald, T. V. <strong>The dominant negative LQT2 mutation A561V reduces wild-type HERG expression.</strong> J. Biol. Chem. 275: 11241-11248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10753933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10753933</a>] [<a href="https://doi.org/10.1074/jbc.275.15.11241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10753933">Kagan et al. (2000)</a> coexpressed wildtype HERG with the A561V mutant in mammalian cells. Transfection with various cDNA ratios produced HERG K+ current densities that approached a predicted binomial distribution where mutant and wildtype subunits coassembled in a tetramer with nearly complete dominance, and 1 subunit was sufficient to reduce functional activity nearly completely. Moreover, the mutant allele reduced the abundance of coexpressed wildtype HERG in cultured mammalian cells, both by decreasing synthesis of full-length protein and by increasing turnover. The effects exerted by the mutant protein were due, at least in part, to misfolding of assembling tetramers and targeting for early degradation, since conditions that facilitated proper folding or inhibitors of the proteasome partially reversed the effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10753933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 LONG QT SYNDROME 2</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">rs121912505 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912505;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=rs121912505" 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=rs121912505" 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=RCV000015502 OR RCV000057902" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015502, RCV000057902" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015502...</a>
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<p>In affected members of a kindred with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> found that an aberrant SSCP conformer was due to an A-to-G substitution at position 1408, a mutation that resulted in substitution of aspartic acid for a conserved asparagine in the second transmembrane domain (N470D). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gong, Q., Jones, M. A., Zhou, Z. <strong>Mechanisms of pharmacological rescue of trafficking-defective hERG mutant channels in human long QT syndrome.</strong> J. Biol. Chem. 281: 4069-4074, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16361248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16361248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16361248[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/10.1074/jbc.M511765200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16361248">Gong et al. (2006)</a> showed that both wildtype and mutant KCNH2 with the N470D substitution associated with the endoplasmic reticulum chaperone protein calnexin (CANX; <a href="/entry/114217">114217</a>). However, the mutant protein showed prolonged association with calnexin, and like immature wildtype KCNH2, was more sensitive than mature wildtype KCNH2 to trypsin digestion. <a href="#9" class="mim-tip-reference" title="Gong, Q., Jones, M. A., Zhou, Z. <strong>Mechanisms of pharmacological rescue of trafficking-defective hERG mutant channels in human long QT syndrome.</strong> J. Biol. Chem. 281: 4069-4074, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16361248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16361248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16361248[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/10.1074/jbc.M511765200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16361248">Gong et al. (2006)</a> concluded that aberrant protein folding increases the association of mutant KCNH2 with calnexin and results in defective protein trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16361248" 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">rs794728391 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728391;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=rs794728391" 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=rs794728391" 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=RCV000015503 OR RCV000181858" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015503, RCV000181858" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015503...</a>
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<p>In a patient with sporadic long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> found that the cause of an aberrant HERG SSCP conformer was a G-to-C substitution converting GT to CT as the first 2 nucleotides of the splice donor sequence of intron 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" 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 LONG QT SYNDROME 2</strong>
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KCNH2, ILE593ARG
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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> rs28928904 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28928904;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/rs28928904?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=rs28928904" 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=rs28928904" 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=RCV000015504 OR RCV000057986 OR RCV001545123 OR RCV001851874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015504, RCV000057986, RCV001545123, RCV001851874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015504...</a>
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<p>In 8 members of 3 generations of a family with long QT syndrome-2 (LQT2; <a href="/entry/613688">613688</a>), <a href="#2" class="mim-tip-reference" title="Benson, D. W., MacRae, C. A., Vesely, M. R., Walsh, E. P., Seidman, J. G., Seidman, C. E., Satler, C. A. <strong>Missense mutation in the pore region of HERG causes familial long QT syndrome.</strong> Circulation 93: 1791-1795, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8635257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8635257</a>] [<a href="https://doi.org/10.1161/01.cir.93.10.1791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8635257">Benson et al. (1996)</a> demonstrated a 1961T-G transversion in the HERG gene resulting in an ile593-to-arg amino acid substitution in the channel pore region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8635257" 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 LONG QT SYNDROME 2</strong>
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KCNH2, VAL822MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912506 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912506;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=rs121912506" 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=rs121912506" 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=RCV000015505 OR RCV000058125 OR RCV000254122 OR RCV000509399 OR RCV000806677 OR RCV001544763" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015505, RCV000058125, RCV000254122, RCV000509399, RCV000806677, RCV001544763" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015505...</a>
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<p><a href="#34" class="mim-tip-reference" title="Satler, C. A., Walsh, E. P., Vesely, M. R., Plummer, M. H., Ginsburg, G. S., Jacob, H. J. <strong>Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome.</strong> Am. J. Med. Genet. 65: 27-35, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8914737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8914737</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8914737">Satler et al. (1996)</a> described a large Irish family with long QT syndrome. The disorder in this family was linked to chromosome 7q35-q36, establishing the phenotype as LQT2 (<a href="/entry/613688">613688</a>). SSCP analysis of the HERG gene showed a G-to-A change at position 2647 resulting in a substitution of methionine for valine at codon 822 and changing the cyclic nucleotide binding domain of the HERG protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8914737" 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="0006" class="mim-anchor"></a>
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<strong>.0006 LONG QT SYNDROME 2</strong>
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KCNH2, 27-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs794728438 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728438;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=rs794728438" 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=rs794728438" 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=RCV000015506 OR RCV000181976 OR RCV003647757" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015506, RCV000181976, RCV003647757" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015506...</a>
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<p>In affected members of a kindred with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> found that an aberrant SSCP conformer resulted from a 27-bp deletion at position 1500. This deletion causes an in-frame deletion of 9 amino acids in the third membrane-spanning domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" 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">rs1554426258 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554426258;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=rs1554426258" 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=rs1554426258" 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=RCV000015507 OR RCV005089262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015507, RCV005089262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015507...</a>
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<p>In affected members of a kindred with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> found that an aberrant SSCP conformer resulted from a 1-bp deletion at position 1261. This deletion causes a frameshift followed by a stop codon 12 amino acids downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" 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="#23" class="mim-tip-reference" title="Li, X., Xu, J., Li, M. <strong>The human delta-1261 mutation of the HERG potassium channel results in a truncated protein that contains a subunit interaction domain and decreases the channel expression.</strong> J. Biol. Chem. 272: 705-708, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8995352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8995352</a>] [<a href="https://doi.org/10.1074/jbc.272.2.705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8995352">Li et al. (1997)</a> found that truncated HERG proteins, including the deletion mutant at position 1261, contain the NAB domain, which is responsible for HERG oligomerization, but lack the rest of the channel and thus inhibit expression of functional tetrameric HERG channels in transfected cells. The authors suggested that LQT may be the result of decreased expression of a functional HERG potassium channel in the heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8995352" 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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KCNH2, GLY628SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912507 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912507;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=rs121912507" 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=rs121912507" 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=RCV000015508 OR RCV000058029 OR RCV000223848 OR RCV000822422 OR RCV002408467 OR RCV004549371 OR RCV004558262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015508, RCV000058029, RCV000223848, RCV000822422, RCV002408467, RCV004549371, RCV004558262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015508...</a>
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<p>In a patient with sporadic long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#5" class="mim-tip-reference" title="Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. <strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong> Cell 80: 795-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90358-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889573">Curran et al. (1995)</a> found that the cause of an aberrant HERG SSCP conformer was a G-to-A substitution at position 1882 converting glycine-628 to serine. This amino acid residue is known to be critical for potassium ion selectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" 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="0009" class="mim-anchor"></a>
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<strong>.0009 LONG QT SYNDROME 2</strong>
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KCNH2, ARG582CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912508 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912508;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=rs121912508" 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=rs121912508" 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=RCV000015509 OR RCV000057970 OR RCV000181815 OR RCV000537059 OR RCV002399326" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015509, RCV000057970, RCV000181815, RCV000537059, RCV002399326" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015509...</a>
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<p>In affected members of 2 Dutch families with long QT syndrome-2 (LQT2; <a href="/entry/613688">613688</a>), <a href="#17" class="mim-tip-reference" title="Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. <strong>Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.</strong> Hum. Mutat. 13: 301-310, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220144</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220144">Jongbloed et al. (1999)</a> identified an arg582-to-cys mutation in the KCNH2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220144" 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>.0010 LONG QT SYNDROME 2</strong>
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KCNH2, GLY572ARG
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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> rs9333649 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9333649;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/rs9333649?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=rs9333649" 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=rs9333649" 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=RCV000015510 OR RCV000057960" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015510, RCV000057960" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015510...</a>
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<p><a href="#21" class="mim-tip-reference" title="Larsen, L. A., Svendsen, I. H., Jensen, A. M., Kanters, J. K., Andersen, P. S., Moller, M., Sorensen, S. A., Sandoe, E., Jacobsen, J. R., Vuust, J., Christiansen, M. <strong>Long QT syndrome with a high mortality rate caused by a novel G572R missense mutation in KCNH2.</strong> Clin. Genet. 57: 125-130, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10735633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10735633</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2000.570206.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10735633">Larsen et al. (2000)</a> reported a 4-generation family with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>) in which affected members had syncopes and torsade de pointes ventricular tachycardia elicited by abrupt awakening in the early morning hours. The authors identified a gly572-to-arg (G572R) missense mutation at the end of the S5 transmembrane segment of the HERG K+ channel in affected family members. Electrocardiograms (ECGs) of affected persons showed prolonged QT interval and notched T waves. Despite treatment with atenolol, 200 mg twice daily, the proband still experienced torsade de pointes ventricular tachycardia. Three untreated relatives had died suddenly and unexpectedly at 18, 32, and 57 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10735633" 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="0011" class="mim-anchor"></a>
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<strong>.0011 LONG QT SYNDROME, BRADYCARDIA-INDUCED</strong>
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KCNH2, ALA490THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28928905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28928905;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=rs28928905" 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=rs28928905" 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=RCV000015511 OR RCV000057910 OR RCV000182022 OR RCV000703745 OR RCV000709729 OR RCV002390110" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015511, RCV000057910, RCV000182022, RCV000703745, RCV000709729, RCV002390110" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015511...</a>
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<p><a href="#48" class="mim-tip-reference" title="Yoshida, H., Horie, M., Otani, H., Kawashima, T., Onishi, Y., Sasayama, S. <strong>Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG.</strong> Am. J. Med. Genet. 98: 348-352, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170080</a>] [<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<348::aid-ajmg1109>3.0.co;2-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170080">Yoshida et al. (2001)</a> reported a 27-year-old patient with bradycardia-induced long QT syndrome (LQT2; <a href="/entry/613688">613688</a>) with a de novo HERG mutation. A 1468G-A substitution in exon 6 of the KCNH2 gene resulted in an ala490-to-thr (A490T) mutation in the S2-S3 inner loop of HERG. The authors suggested that this mutation may cause subtle changes in HERG channel functions in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170080" 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 LONG QT SYNDROME 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121912509 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912509;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/rs121912509?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=rs121912509" 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=rs121912509" 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=RCV000015512 OR RCV000181905 OR RCV001207958" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015512, RCV000181905, RCV001207958" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015512...</a>
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<p><a href="#19" class="mim-tip-reference" title="Kupershmidt, S., Yang, T., Chanthaphaychith, S., Wang, Z., Towbin, J. A., Roden, D. M. <strong>Defective human ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus.</strong> J. Biol. Chem. 277: 27442-27448, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12021266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12021266</a>] [<a href="https://doi.org/10.1074/jbc.M112375200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12021266">Kupershmidt et al. (2002)</a> studied the pathogenetic mechanisms involved in long QT syndrome (LQT2; <a href="/entry/613688">613688</a>) in a family with a transition mutation at nucleotide 3003 of the HERG gene, converting codon 1001 from TGG (trp) to TGA (ter). They concluded that the C terminus of HERG contains an RXR motif which, when exposed by mutation, results in reduced cell surface trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12021266" 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>.0013 LONG QT SYNDROME 2</strong>
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KCNH2, SER818LEU
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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> rs121912510 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912510;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/rs121912510?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=rs121912510" 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=rs121912510" 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=RCV000015513 OR RCV000058123 OR RCV000631649 OR RCV002426506 OR RCV003591634 OR RCV004696637" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015513, RCV000058123, RCV000631649, RCV002426506, RCV003591634, RCV004696637" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015513...</a>
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<p><a href="#3" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> identified a ser818-to-leu (S818L) mutation, located in the putative cyclic nucleotide binding domain in the HERG C terminus, in patients with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>). <a href="#27" class="mim-tip-reference" title="Nakajima, T., Kurabayashi, M., Ohyama, Y., Kaneko, Y., Furukawa, T., Itoh, T., Taniguchi, Y., Tanaka, T., Nakamura, Y., Hiraoka, M., Nagai, R. <strong>Characterization of S818L mutation in HERG C-terminus in LQT2: modification of activation-deactivation gating properties.</strong> FEBS Lett. 481: 197-203, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10996323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10996323</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01988-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10996323">Nakajima et al. (2000)</a> found the same mutation in Japanese LQT2 patients and examined the mechanism for HERG channel dysfunction, using the heterologous expression system in Xenopus oocytes. The data suggested that S818L alone cannot form functional channels, whereas S818L subunits can, at least in part, coassemble with wildtype subunits to form heterotetrameric functional channels. The data also implied that the HERG C terminus may contain a domain involving the activation-deactivation process of the channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10086971+10996323" 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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<span class="mim-font">
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<strong>.0014 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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KCNH2, ARG784TRP
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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> rs12720441 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12720441;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/rs12720441?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=rs12720441" 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=rs12720441" 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=RCV000058108 OR RCV000208497 OR RCV001262685 OR RCV001841245 OR RCV001851875 OR RCV002223758 OR RCV003162252 OR RCV004549372 OR RCV004720231" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000058108, RCV000208497, RCV001262685, RCV001841245, RCV001851875, RCV002223758, RCV003162252, RCV004549372, RCV004720231" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000058108...</a>
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<p>This variant, formerly titled LONG QT SYNDROME 2, ACQUIRED, SUSCEPTIBILITY TO, has been reclassified based on the article by <a href="#20" class="mim-tip-reference" title="Lacaze, P., Sebra, R., Riaz, M., Ingles, J., Tiller, J., Thompson, B. A., James, P. A., Fatkin, D., Semsarian, C., Reid, C. M., Tonkin, A. M., Winship, I., Schadt, E., McNeil, J. J. <strong>Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.</strong> NPJ Genomic Med. 6: 51, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34135346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34135346</a>] [<a href="https://doi.org/10.1038/s41525-021-00211-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34135346">Lacaze et al. (2021)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34135346" 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="#47" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al. (2002)</a> described an individual who developed QT prolongation and torsade de pointes while taking the drug amiodarone (see <a href="/entry/613688">613688</a>). The ECG abnormalities reversed on drug withdrawal. Analysis of the coding sequence of the gene encoding HERG revealed a C-to-T transition at nucleotide position 2350, which resulted in an arginine-to-tryptophan substitution at amino acid position 784 (R784W). The mutation was not found in 228 controls. In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents. These findings suggested that the R784W mutation was responsible for the patient's response to amiodarone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults (mean age, 75 years) of European descent, <a href="#20" class="mim-tip-reference" title="Lacaze, P., Sebra, R., Riaz, M., Ingles, J., Tiller, J., Thompson, B. A., James, P. A., Fatkin, D., Semsarian, C., Reid, C. M., Tonkin, A. M., Winship, I., Schadt, E., McNeil, J. J. <strong>Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.</strong> NPJ Genomic Med. 6: 51, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34135346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34135346</a>] [<a href="https://doi.org/10.1038/s41525-021-00211-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34135346">Lacaze et al. (2021)</a> identified the R784W variant in 3 alleles, thus calling its pathogenicity into question. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34135346" 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 LONG QT SYNDROME 2</strong>
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KCNH2, THR65PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912511 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912511;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=rs121912511" 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=rs121912511" 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=RCV000015515 OR RCV000058063" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015515, RCV000058063" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015515...</a>
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<p>In a patient with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#28" class="mim-tip-reference" title="Paulussen, A., Raes, A., Matthijs, G., Snyders, D. J., Cohen, N., Aerssens, J. <strong>A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.</strong> J. Biol. Chem. 277: 48610-48616, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12354768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12354768</a>] [<a href="https://doi.org/10.1074/jbc.M206569200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12354768">Paulussen et al. (2002)</a> identified and characterized a novel 193A-C transversion in exon 2 of the PAS domain of the HERG gene causing a thr65-to-pro (T65P) substitution and resulting in defective trafficking of the protein to the cell membrane. Defective folding of the mutant protein could be restored by decreased cell incubation temperature and pharmacologically. When trafficking was restored by growing cells at 27 degrees C, the kinetics of the mutated channel resembled that of wildtype channels although the rates of activation, deactivation, and recovery from inactivation were accelerated. No positive evidence for the formation of heterotetramers was obtained by coexpression of wildtype with mutant subunits at 37 degrees C. As a consequence, the clinical symptoms may be explained by haploinsufficiency rather than by dominant-negative effects. <a href="#28" class="mim-tip-reference" title="Paulussen, A., Raes, A., Matthijs, G., Snyders, D. J., Cohen, N., Aerssens, J. <strong>A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.</strong> J. Biol. Chem. 277: 48610-48616, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12354768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12354768</a>] [<a href="https://doi.org/10.1074/jbc.M206569200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12354768">Paulussen et al. (2002)</a> stated that 6 trafficking-deficient mutations had previously been described in the HERG gene and that this study was the first to relate a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12354768" 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> rs121912512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912512;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/rs121912512?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=rs121912512" 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=rs121912512" 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=RCV000015516 OR RCV000058100 OR RCV000148536 OR RCV001659699" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015516, RCV000058100, RCV000148536, RCV001659699" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015516...</a>
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<p>In an infant with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>) who was initially referred at 38 weeks' gestation for irregular heartbeat, <a href="#16" class="mim-tip-reference" title="Johnson, W. H., Jr., Yang, P., Yang, T., Lau, Y. B., Mostella, B. A., Wolff, D. J., Roden, D. M., Benson, D. W. <strong>Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome.</strong> Pediat. Res. 53: 744-748, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12621127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12621127</a>] [<a href="https://doi.org/10.1203/01.PDR.0000059750.17002.B6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12621127">Johnson et al. (2003)</a> found a homozygous G-to-A transition at nucleotide 2255 of the HERG gene resulting in an arg752-to-gln (R752Q) substitution. The heterozygous mother and maternal aunt and grandmother had normal ECGs and were asymptomatic, and there was no family history suggestive of LQTS. Maternal isodisomy was excluded. The absent father was said to be healthy. All 4 individuals with the R752Q mutation also had the G643S HERG polymorphism (<a href="#14" class="mim-tip-reference" title="Itoh, T., Tanaka, T., Nagai, R., Kamiya, T., Sawayama, T., Nakayama, T., Tomoike, H., Sakurada, H., Yazaki, Y., Nakamura, Y. <strong>Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome.</strong> Hum. Genet. 102: 435-439, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600240</a>] [<a href="https://doi.org/10.1007/s004390050717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600240">Itoh et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9600240+12621127" 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">rs104894021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894021;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=rs104894021" 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=rs104894021" 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=RCV000015517 OR RCV000057981 OR RCV004991976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015517, RCV000057981, RCV004991976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015517...</a>
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<p>In 2 families with short QT syndrome-1 (SQT1; <a href="/entry/609620">609620</a>), previously reported by <a href="#7" class="mim-tip-reference" title="Gaita, F., Giustetto, C., Bianchi, F., Wolpert, C., Schimpf, R., Riccardi, R., Grossi, S., Richiardi, E., Borggrefe, M. <strong>Short QT syndrome: a familial cause of sudden death.</strong> Circulation 108: 965-970, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925462</a>] [<a href="https://doi.org/10.1161/01.CIR.0000085071.28695.C4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925462">Gaita et al. (2003)</a>, <a href="#4" class="mim-tip-reference" title="Brugada, R., Hong, K., Dumaine, R., Cordeiro, J., Gaita, F., Borggrefe, M., Menendez, T. M., Brugada, J., Pollevick, G. D., Wolpert, C., Burashnikov, E., Matsuo, K., Wu, Y. S., Guerchicoff, A., Bianchi, F., Giustetto, C., Schimpf, R., Brugada, P., Antzelevitch, C. <strong>Sudden death associated with short-QT syndrome linked to mutations in HERG.</strong> Circulation 109: 30-35, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676148</a>] [<a href="https://doi.org/10.1161/01.CIR.0000109482.92774.3A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676148">Brugada et al. (2004)</a> identified respective 1764C-G and 1764C-A (<a href="#0018">152427.0018</a>) transversions in exon 7 of the KCNH2 gene, leading to the same asn588-to-lys (N588K) substitution in the S5-P loop region of the cardiac I(Kr) channel. The mutation was present in all affected family members and in none of the unaffected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12925462+14676148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family with short QT syndrome, originally reported by <a href="#11" class="mim-tip-reference" title="Gussak, I., Brugada, P., Brugada, J., Wright, R. S., Kopecky, S. L., Chaitman, B. R., Bjerregaard, P. <strong>Idiopathic short QT interval: a new clinical syndrome?</strong> Cardiology 94: 99-102, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173780</a>] [<a href="https://doi.org/10.1159/000047299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173780">Gussak et al. (2000)</a>, <a href="#12" class="mim-tip-reference" title="Hong, K., Bjerregaard, P., Gussak, I., Brugada, R. <strong>Short QT syndrome and atrial fibrillation caused by mutation in KCNH2.</strong> J. Cardiovasc. Electrophysiol. 16: 394-396, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15828882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15828882</a>] [<a href="https://doi.org/10.1046/j.1540-8167.2005.40621.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15828882">Hong et al. (2005)</a> identified the 1764C-G transversion in the KCNH2 gene and concluded that N588K is a hotspot for this familial form of short QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15828882+11173780" 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">rs104894021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894021;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=rs104894021" 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=rs104894021" 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=RCV000015518 OR RCV000057980 OR RCV004991977" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015518, RCV000057980, RCV004991977" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015518...</a>
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<p>In 2 families with short QT syndrome-1 (SQT1; <a href="/entry/609620">609620</a>), previously reported by <a href="#7" class="mim-tip-reference" title="Gaita, F., Giustetto, C., Bianchi, F., Wolpert, C., Schimpf, R., Riccardi, R., Grossi, S., Richiardi, E., Borggrefe, M. <strong>Short QT syndrome: a familial cause of sudden death.</strong> Circulation 108: 965-970, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925462</a>] [<a href="https://doi.org/10.1161/01.CIR.0000085071.28695.C4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925462">Gaita et al. (2003)</a>, <a href="#4" class="mim-tip-reference" title="Brugada, R., Hong, K., Dumaine, R., Cordeiro, J., Gaita, F., Borggrefe, M., Menendez, T. M., Brugada, J., Pollevick, G. D., Wolpert, C., Burashnikov, E., Matsuo, K., Wu, Y. S., Guerchicoff, A., Bianchi, F., Giustetto, C., Schimpf, R., Brugada, P., Antzelevitch, C. <strong>Sudden death associated with short-QT syndrome linked to mutations in HERG.</strong> Circulation 109: 30-35, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676148</a>] [<a href="https://doi.org/10.1161/01.CIR.0000109482.92774.3A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676148">Brugada et al. (2004)</a> identified respective 1764C-G (<a href="#0017">152427.0017</a>) and 1764C-A transversions in exon 7 of the KCNH2 gene, leading to the same asn588-to-lys (N588K) substitution in the S5-P loop region of the cardiac I(Kr) channel. The mutation was present in all affected family members and in none of the unaffected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12925462+14676148" 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">rs1554424772 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554424772;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=rs1554424772" 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=rs1554424772" 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=RCV000015519 OR RCV003531902 OR RCV004719649" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015519, RCV003531902, RCV004719649" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015519...</a>
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<p>In 2 severely affected sisters from a large Belgian family with long QT syndrome (see <a href="/entry/613688">613688</a>), <a href="#3" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> identified biallelic digenic mutations: a +1G-A transition at the donor splice site in IVS10 of the KCNH2 gene (2592+1G-A), and an A341E substitution in the KCNQ1 gene (<a href="/entry/607542#0009">607542.0009</a>). The father and his affected relatives were heterozygous for the A341E mutation in KCNQ1; the mother, a more mildly affected sister, and a grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected family members, and the KCNH2 splice site mutation was not found in more than 100 unrelated controls. <a href="#3" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> stated that this was the first description of double heterozygosity in long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10086971" 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> rs794728455 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794728455;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/rs794728455?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=rs794728455" 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=rs794728455" 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=RCV000015520 OR RCV000015521 OR RCV000181993 OR RCV000204205 OR RCV000249424 OR RCV001842847" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015520, RCV000015521, RCV000181993, RCV000204205, RCV000249424, RCV001842847" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015520...</a>
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<p>In a patient with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#36" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. <strong>Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.</strong> Circulation 102: 1178-1185, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973849</a>] [<a href="https://doi.org/10.1161/01.cir.102.10.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973849">Splawski et al. (2000)</a> identified heterozygosity for a 1-bp insertion (2775insG) in exon 12 of the KCNH2 gene, causing a frameshift at pro926 that results in a termination signal 13 codons downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female infant with a family history of sudden death, who had severe, continuous bradycardia in utero that was confirmed after birth and a QTc of 485 ms, <a href="#24" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: 2775insG in the KCNH2 gene and a deletion in the KCNQ1 gene (562delT; <a href="/entry/607542#0038">607542.0038</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" 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">rs121912513 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912513;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=rs121912513" 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=rs121912513" 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=RCV000015522 OR RCV000015523 OR RCV000058141 OR RCV002223759 OR RCV002490375 OR RCV003531903" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015522, RCV000015523, RCV000058141, RCV002223759, RCV002490375, RCV003531903" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015522...</a>
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<p>In a patient with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#36" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. <strong>Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.</strong> Circulation 102: 1178-1185, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973849</a>] [<a href="https://doi.org/10.1161/01.cir.102.10.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973849">Splawski et al. (2000)</a> identified heterozygosity for a 2582A-T transversion in exon 10 of the KCNH2 gene, resulting in an asn861-to-ile (N861I) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female patient who had a QTc of 460 ms and suffered cardiac arrest, <a href="#45" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> identified triallelic digenic mutations: heterozygosity for an N861I substitution in the KCNH2 gene and homozygosity for a missense mutation in the KCNE1 gene (D85N; <a href="/entry/176261#0005">176261.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15051636" 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> rs121912514 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912514;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/rs121912514?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=rs121912514" 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=rs121912514" 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=RCV000015524 OR RCV000058169 OR RCV001318613 OR RCV001794448 OR RCV001841246 OR RCV002496372" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015524, RCV000058169, RCV001318613, RCV001794448, RCV001841246, RCV002496372" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015524...</a>
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<p>In a female infant with fetal and neonatal bradycardia and a QTc of 570 ms (see <a href="/entry/613688">613688</a>), <a href="#24" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: a 2841C-T transition in exon 12 of the KCNH2 gene, resulting in an arg948-to-cys (R948C) substitution, and a missense mutation in the KCNQ1 gene (R243P; <a href="/entry/607542#0039">607542.0039</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" 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>.0023 LONG QT SYNDROME 2/3, DIGENIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121912515 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912515;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/rs121912515?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=rs121912515" 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=rs121912515" 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=RCV000015525 OR RCV000058186 OR RCV000181948 OR RCV000617723 OR RCV002247344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015525, RCV000058186, RCV000181948, RCV000617723, RCV002247344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015525...</a>
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<p>In a 41-year-old female who had cardiac arrest due to torsade de pointes triggered by exercise and leading to ventricular fibrillation, and a QTc of 520 ms (see <a href="/entry/613688">613688</a>), <a href="#24" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: a 298C-G transversion in exon 2 of the KCNH2 gene, resulting in an arg100-to-gly (R100G) substitution, and a missense mutation in the SCN5A gene (D1819N; <a href="/entry/600163#0035">600163.0035</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" 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> rs77331749 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77331749;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/rs77331749?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=rs77331749" 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=rs77331749" 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=RCV000015526 OR RCV000015527 OR RCV000058156 OR RCV000204621 OR RCV000589886 OR RCV000620709 OR RCV001841247" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015526, RCV000015527, RCV000058156, RCV000204621, RCV000589886, RCV000620709, RCV001841247" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015526...</a>
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<p>In 2 unrelated patients with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#40" class="mim-tip-reference" title="Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. <strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong> Heart Rhythm 2: 507-517, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840476</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.01.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840476">Tester et al. (2005)</a> identified a 2738C-T transition in exon 12 of the KCNH2 gene, resulting in an ala913-to-val (A913V) substitution in the C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15840476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 14-year-old girl with long QT syndrome (see <a href="/entry/613688">613688</a>), <a href="#43" class="mim-tip-reference" title="Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. <strong>Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.</strong> Circulation 114: 2104-2112, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17060380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17060380</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.635268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17060380">Vatta et al. (2006)</a> identified biallelic digenic mutations: the A913V mutation in the KCNH2 gene and a T78M mutation in the LQT9-associated CAV3 gene (<a href="/entry/601253#0018">601253.0018</a>). The patient had nonexertional syncope and a 'seizure-like' presentation, with U waves, sinus bradycardia, and a QTc of 405 ms on ECG; she had a positive family history, but family members declined further genotyping. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" 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">rs121912516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912516;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=rs121912516" 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=rs121912516" 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=RCV000015528 OR RCV000057935" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015528, RCV000057935" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015528...</a>
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<p>In a 3-generation Dutch family with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#17" class="mim-tip-reference" title="Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. <strong>Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.</strong> Hum. Mutat. 13: 301-310, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220144</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220144">Jongbloed et al. (1999)</a> identified heterozygosity for a 1672G-C transversion in exon 7 of the KCNH2 gene, resulting in an ala558-to-pro (A558P) substitution. The index patient was a 22-year-old woman who had died suddenly upon arousal from sleep by an alarm clock. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Amin, A. S., Herfst, L. J., Delisle, B. P., Klemens, C. A., Rook, M. B., Bezzina, C. R., Underkofler, H. A. S., Holzem, K. M., Ruijter, J. M., Tan, H. L., January, C. T., Wilde, A. A. M. <strong>Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.</strong> J. Clin. Invest. 118: 2552-2561, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18551196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18551196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18551196[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/JCI35337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18551196">Amin et al. (2008)</a> reported that the father and brother of the index patient described by <a href="#17" class="mim-tip-reference" title="Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. <strong>Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.</strong> Hum. Mutat. 13: 301-310, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220144</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220144">Jongbloed et al. (1999)</a>, both carriers of the A558P mutation, suffered repeated occurrences of fever-induced syncope, polymorphic ventricular tachycardia, and ventricular fibrillation. Electrocardiography showed increased QTc with fever in both patients. Studies in HEK293 cells showed that the A558P protein has a trafficking-deficient phenotype. Coexpression of A558P and wildtype proteins demonstrated a dominant-negative effect of the mutation, a selectively accelerated rate of channel inactivation, and reduced temperature-dependent increase in the wildtype current. <a href="#1" class="mim-tip-reference" title="Amin, A. S., Herfst, L. J., Delisle, B. P., Klemens, C. A., Rook, M. B., Bezzina, C. R., Underkofler, H. A. S., Holzem, K. M., Ruijter, J. M., Tan, H. L., January, C. T., Wilde, A. A. M. <strong>Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.</strong> J. Clin. Invest. 118: 2552-2561, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18551196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18551196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18551196[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/JCI35337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18551196">Amin et al. (2008)</a> suggested that the weak increase in HERG current density in wildtype-mutant coassembled channels contributed to the development of QTc prolongation and arrhythmias at febrile temperatures. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10220144+18551196" 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">rs199472944 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199472944;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=rs199472944" 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=rs199472944" 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=RCV000022643 OR RCV000058010 OR RCV000254785 OR RCV000462085 OR RCV002408476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022643, RCV000058010, RCV000254785, RCV000462085, RCV002408476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022643...</a>
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<p><a href="#38" class="mim-tip-reference" title="Tanaka, T., Nagai, R., Tomoike, H., Takata, S., Yano, K., Yabuta, K., Haneda, N., Nakano, O., Shibata, A., Sawayama, T., Kasai, H., Yazaki, Y., Nakamura, Y. <strong>Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.</strong> Circulation 95: 565-567, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024139</a>] [<a href="https://doi.org/10.1161/01.cir.95.3.565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9024139">Tanaka et al. (1997)</a> identified a C-to-T transition in exon 9 of the KCNH2 gene resulting in an alanine-to-valine substitution at codon 614 (A614V) in a member of a cohort of Japanese patients with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>). This same mutation was identified in an Israeli family with long QT syndrome by <a href="#39" class="mim-tip-reference" title="Tenenbaum, M., Lavi, S., Magal, N., Halpern, G. J., Bolocan, I., Boulos, M., Kapeliovich, M., Shohat, M., Hammerman, H. <strong>Identification of the gene causing long QT syndrome in an Israeli family.</strong> Isr. Med. Assoc. J. 10: 809-811, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19070294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19070294</a>]" pmid="19070294">Tenenbaum et al. (2008)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19070294+9024139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., Feldman, O., Gepstein, A., Arbel, G., Hammerman, H., Boulos, M., Gepstein, L. <strong>Modelling the long QT syndrome with induced pluripotent stem cells.</strong> Nature 471: 225-229, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21240260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21240260</a>] [<a href="https://doi.org/10.1038/nature09747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21240260">Itzhaki et al. (2011)</a> developed a patient/disease-specific human induced pluripotent stem cell (iPSC) line from a patient with LQT2 due to an A614V missense mutation in the KCNH2 gene. The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action potential duration in LQTS human iPSC-derived cardiomyocytes when compared to healthy control cells. Voltage-clamp studies confirmed that this action potential duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. <a href="#15" class="mim-tip-reference" title="Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., Feldman, O., Gepstein, A., Arbel, G., Hammerman, H., Boulos, M., Gepstein, L. <strong>Modelling the long QT syndrome with induced pluripotent stem cells.</strong> Nature 471: 225-229, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21240260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21240260</a>] [<a href="https://doi.org/10.1038/nature09747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21240260">Itzhaki et al. (2011)</a> then used the LQTS human iPSC-derived cardiac tissue model to evaluate the potency of existing and novel pharmacologic agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers, and late sodium-channel blockers) the disease phenotype. <a href="#15" class="mim-tip-reference" title="Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., Feldman, O., Gepstein, A., Arbel, G., Hammerman, H., Boulos, M., Gepstein, L. <strong>Modelling the long QT syndrome with induced pluripotent stem cells.</strong> Nature 471: 225-229, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21240260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21240260</a>] [<a href="https://doi.org/10.1038/nature09747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21240260">Itzhaki et al. (2011)</a> concluded that their study illustrated the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21240260" 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>.0027 LONG QT SYNDROME 2</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">rs199472942 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199472942;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=rs199472942" 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=rs199472942" 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=RCV000022644 OR RCV000058006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022644, RCV000058006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022644...</a>
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<p>In a Japanese family with long QT syndrome (LQT2; <a href="/entry/613688">613688</a>), <a href="#38" class="mim-tip-reference" title="Tanaka, T., Nagai, R., Tomoike, H., Takata, S., Yano, K., Yabuta, K., Haneda, N., Nakano, O., Shibata, A., Sawayama, T., Kasai, H., Yazaki, Y., Nakamura, Y. <strong>Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.</strong> Circulation 95: 565-567, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024139</a>] [<a href="https://doi.org/10.1161/01.cir.95.3.565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9024139">Tanaka et al. (1997)</a> identified a T-to-C transition in the KCNH2 gene, resulting in a tyr611-to-his (Y611H) substitution between the S5 and pore regions of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9024139" 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="#50" class="mim-tip-reference" title="Zhou, Z., Gong, Q., Epstein, M. L., January, C. T. <strong>HERG channel dysfunction in human long QT syndrome: intracellular transport and functional defects.</strong> J. Biol. Chem. 273: 21061-21066, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694858</a>] [<a href="https://doi.org/10.1074/jbc.273.33.21061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9694858">Zhou et al. (1998)</a> found that the Y611H mutation in KCNH2 resulted in defective biosynthetic processing, with the protein retained in the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9694858" 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="Gong, Q., Keeney, D. R., Molinari, M., Zhou, Z. <strong>Degradation of trafficking-defective long QT syndrome type II mutant channels by the ubiquitin-proteasome pathway.</strong> J. Biol. Chem. 280: 19419-19425, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15760896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15760896</a>] [<a href="https://doi.org/10.1074/jbc.M502327200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15760896">Gong et al. (2005)</a> found that KCNH2 with the Y611H mutation was deglycosylated, ubiquitinated, and degraded via the proteasome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15760896" 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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<strong>Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.</strong>
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J. Clin. Invest. 118: 2552-2561, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18551196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18551196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18551196[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=18551196" 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/10.1172/JCI35337" target="_blank">Full Text</a>]
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Benson, D. W., MacRae, C. A., Vesely, M. R., Walsh, E. P., Seidman, J. G., Seidman, C. E., Satler, C. A.
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<strong>Missense mutation in the pore region of HERG causes familial long QT syndrome.</strong>
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Circulation 93: 1791-1795, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8635257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8635257</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8635257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.93.10.1791" target="_blank">Full Text</a>]
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Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P.
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<strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong>
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Circulation 99: 1464-1470, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10086971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Brugada, R., Hong, K., Dumaine, R., Cordeiro, J., Gaita, F., Borggrefe, M., Menendez, T. M., Brugada, J., Pollevick, G. D., Wolpert, C., Burashnikov, E., Matsuo, K., Wu, Y. S., Guerchicoff, A., Bianchi, F., Giustetto, C., Schimpf, R., Brugada, P., Antzelevitch, C.
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<strong>Sudden death associated with short-QT syndrome linked to mutations in HERG.</strong>
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Circulation 109: 30-35, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676148</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T.
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<strong>A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.</strong>
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Cell 80: 795-803, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889573</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ficker, E., Dennis, A. T., Wang, L., Brown, A. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925462</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12925462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Rescue of aberrant gating by a genetically encoded PAS (Per-Arnt-Sim) domain in several long QT syndrome mutant human ether-a-go-go-related gene potassium channels.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21536673[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=21536673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gong, Q., Jones, M. A., Zhou, Z.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16361248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16361248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16361248[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=16361248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M511765200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M502327200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1540-8167.2005.40621.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050717" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.7604285" target="_blank">Full Text</a>]
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</p>
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<a id="43" class="mim-anchor"></a>
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<a id="Vatta2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A.
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<strong>Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.</strong>
|
|
Circulation 114: 2104-2112, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17060380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17060380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.635268" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="44" class="mim-anchor"></a>
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<a id="Warmke1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Warmke, J. W., Ganetzky, B.
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<strong>A family of potassium channel genes related to eag in Drosophila and mammals.</strong>
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Proc. Nat. Acad. Sci. 91: 3438-3442, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8159766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8159766</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8159766" 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.91.8.3438" target="_blank">Full Text</a>]
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<li>
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<a id="45" class="mim-anchor"></a>
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<a id="Westenskow2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C.
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<strong>Compound mutations: a common cause of severe long-QT syndrome.</strong>
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Circulation 109: 1834-1841, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15051636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank">Full Text</a>]
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<li>
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<a id="46" class="mim-anchor"></a>
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<a id="Xiao2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xiao, J., Luo, X., Lin, H., Zhang, Y., Lu, Y., Wang, N., Zhang, Y., Yang, B., Wang, Z.
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<strong>MicroRNA miR-133 represses HERG K(+) channel expression contributing to QT prolongation in diabetic hearts.</strong>
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J. Biol. Chem. 282: 12363-12367, 2007. Note: Retraction: J. Biol. Chem. 286: 28656 only, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344217</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.C700015200" target="_blank">Full Text</a>]
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<a id="47" class="mim-anchor"></a>
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<a id="Yang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M.
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<strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong>
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Circulation 105: 1943-1948, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank">Full Text</a>]
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<a id="48" class="mim-anchor"></a>
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<a id="Yoshida2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yoshida, H., Horie, M., Otani, H., Kawashima, T., Onishi, Y., Sasayama, S.
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<strong>Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG.</strong>
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Am. J. Med. Genet. 98: 348-352, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<348::aid-ajmg1109>3.0.co;2-a" target="_blank">Full Text</a>]
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<a id="49" class="mim-anchor"></a>
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<a id="Zareba1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zareba, W., Moss, A. J., Schwartz, P. J., Vincent, G. M., Robinson, J. L., Priori, S. G., Benhorin, J., Locati, E. H., Towbin, J. A., Keating, M. T., Lehmann, M. H., Hall, W. J., International Long-QT Syndrome Registry Research Group.
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<strong>Influence of the genotype on the clinical course of the long-QT syndrome.</strong>
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New Eng. J. Med. 339: 960-965, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199810013391404" target="_blank">Full Text</a>]
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<a id="50" class="mim-anchor"></a>
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<a id="Zhou1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, Z., Gong, Q., Epstein, M. L., January, C. T.
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<strong>HERG channel dysfunction in human long QT syndrome: intracellular transport and functional defects.</strong>
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J. Biol. Chem. 273: 21061-21066, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694858</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9694858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.33.21061" target="_blank">Full Text</a>]
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</ol>
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<br />
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</div>
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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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Patricia A. Hartz - updated : 4/26/2016
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 3/25/2016<br>Marla J. F. O'Neill - updated : 3/28/2014<br>Matthew B. Gross - updated : 1/17/2012<br>Patricia A. Hartz - updated : 10/6/2011<br>Ada Hamosh - updated : 6/14/2011<br>Ada Hamosh - updated : 2/1/2010<br>Cassandra L. Kniffin - updated : 5/21/2009<br>Marla J. F. O'Neill - updated : 12/19/2008<br>Marla J. F. O'Neill - updated : 11/21/2008<br>Marla J. F. O'Neill - updated : 2/12/2008<br>Victor A. McKusick - updated : 2/26/2007<br>Marla J. F. O'Neill - updated : 12/8/2006<br>Marla J. F. O'Neill - updated : 11/9/2006<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Victor A. McKusick - updated : 10/7/2004<br>Marla J. F. O'Neill - updated : 3/3/2004<br>Natalie E. Krasikov - updated : 12/19/2003<br>Victor A. McKusick - updated : 5/2/2003<br>Victor A. McKusick - updated : 2/12/2003<br>Paul Brennan - updated : 12/4/2002<br>Paul Brennan - updated : 12/4/2002<br>Victor A. McKusick - updated : 9/25/2002<br>Paul Brennan - updated : 8/7/2002<br>Paul Brennan - updated : 3/14/2002<br>Sonja A. Rasmussen - updated : 3/13/2001<br>Paul J. Converse - updated : 5/23/2000<br>Victor A. McKusick - updated : 4/21/2000<br>Paul Brennan - updated : 4/7/2000<br>Victor A. McKusick - updated : 6/3/1999<br>Victor A. McKusick - updated : 10/2/1998<br>Victor A. McKusick - updated : 9/14/1998<br>Clair A. Francomano - updated : 5/27/1998<br>Victor A. McKusick - updated : 11/17/1997<br>Alan F. Scott - updated : 9/17/1995
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/16/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 09/30/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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carol : 10/20/2022<br>carol : 10/19/2022<br>carol : 10/19/2022<br>carol : 05/04/2022<br>carol : 04/23/2017<br>alopez : 10/10/2016<br>carol : 06/23/2016<br>mgross : 4/26/2016<br>carol : 3/25/2016<br>mcolton : 3/28/2014<br>alopez : 5/24/2013<br>joanna : 12/21/2012<br>terry : 11/27/2012<br>carol : 9/4/2012<br>mgross : 1/17/2012<br>terry : 10/6/2011<br>terry : 7/5/2011<br>alopez : 6/17/2011<br>terry : 6/14/2011<br>carol : 1/14/2011<br>carol : 1/13/2011<br>alopez : 2/5/2010<br>terry : 2/1/2010<br>terry : 12/16/2009<br>wwang : 6/5/2009<br>ckniffin : 5/21/2009<br>wwang : 12/19/2008<br>terry : 12/19/2008<br>alopez : 12/18/2008<br>terry : 11/21/2008<br>carol : 5/14/2008<br>carol : 3/10/2008<br>wwang : 2/26/2008<br>terry : 2/12/2008<br>carol : 12/26/2007<br>wwang : 6/8/2007<br>alopez : 3/8/2007<br>terry : 2/26/2007<br>carol : 2/8/2007<br>wwang : 12/11/2006<br>terry : 12/8/2006<br>carol : 11/22/2006<br>carol : 11/10/2006<br>carol : 11/9/2006<br>wwang : 9/29/2005<br>terry : 9/29/2005<br>terry : 9/29/2005<br>tkritzer : 10/13/2004<br>carol : 10/12/2004<br>tkritzer : 10/12/2004<br>terry : 10/7/2004<br>carol : 3/17/2004<br>carol : 3/3/2004<br>alopez : 12/19/2003<br>cwells : 11/7/2003<br>cwells : 5/5/2003<br>terry : 5/2/2003<br>carol : 2/27/2003<br>tkritzer : 2/24/2003<br>terry : 2/12/2003<br>ckniffin : 2/5/2003<br>alopez : 12/4/2002<br>alopez : 12/4/2002<br>carol : 10/4/2002<br>tkritzer : 9/26/2002<br>tkritzer : 9/25/2002<br>alopez : 8/7/2002<br>alopez : 8/7/2002<br>alopez : 3/14/2002<br>mcapotos : 3/15/2001<br>mcapotos : 3/13/2001<br>carol : 5/25/2000<br>carol : 5/23/2000<br>mcapotos : 5/19/2000<br>mcapotos : 5/17/2000<br>terry : 4/21/2000<br>alopez : 4/7/2000<br>alopez : 4/7/2000<br>alopez : 4/7/2000<br>mgross : 6/3/1999<br>carol : 5/25/1999<br>carol : 5/11/1999<br>alopez : 12/1/1998<br>alopez : 12/1/1998<br>carol : 10/7/1998<br>terry : 10/2/1998<br>alopez : 9/15/1998<br>terry : 9/14/1998<br>terry : 6/1/1998<br>dholmes : 5/27/1998<br>dholmes : 5/27/1998<br>dholmes : 5/12/1998<br>dholmes : 5/6/1998<br>jenny : 11/19/1997<br>terry : 11/17/1997<br>terry : 9/30/1997<br>mark : 3/7/1997<br>jamie : 1/7/1997<br>jamie : 1/6/1997<br>mark : 9/19/1996<br>terry : 9/10/1996<br>terry : 4/17/1996<br>mark : 2/28/1996<br>terry : 2/28/1996<br>mark : 11/2/1995<br>terry : 4/20/1995<br>mimadm : 11/5/1994<br>carol : 9/16/1993
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<h3>
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<span class="mim-font">
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<strong>*</strong> 152427
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<div>
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<h3>
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<span class="mim-font">
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POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 2; KCNH2
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</h3>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HUMAN ETHER-A-GO-GO-RELATED GENE; HERG<br />
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ETHER-A-GO-GO-RELATED GENE, HUMAN<br />
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ERG1<br />
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KV11.1
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</span>
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</h4>
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<strong><em>HGNC Approved Gene Symbol: KCNH2</em></strong>
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<strong>
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<em>
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Cytogenetic location: 7q36.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:150,944,961-150,978,321 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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7q36.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Long QT syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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613688
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Short QT syndrome 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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609620
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>KCNH2 encodes the pore-forming subunit of a rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential (Gianulis and Trudeau, 2011). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Warmke and Ganetzky (1994) identified a novel human cDNA from a hippocampal cDNA library by homology to the Drosophila 'ether-a-go-go' (eag) gene, which encodes a Ca(2+)-modulated potassium channel. The authors called the cDNA HERG (human ether-a-go-go-related gene). </p><p>Huffaker et al. (2009) identified a brain-specific isoform of KCNH2, which they referred to as KCNH2-3.1. The new isoform originates upstream of exon 3 of the known isoform KCNH2-1A and contains all of the downstream exons of the full-length gene through exon 15. In silico prediction of the longest open reading frame of KCNH2-3.1 suggested that the majority of the 5-prime extension of exon 3 is untranslated, and that the first methionine is in-frame with the conserved portion of KCNH2-1A. Thus, KCNH2-3.1 was predicted to be missing the first 102 amino acids of KCNH2-1A, replacing them with 6 unique amino acids. Western blot analysis of human hippocampus and frontal cortex cells confirmed the predicted difference in protein size. The KCNH2-3.1 isoform was preferentially expressed in human brain. It was not detected in mouse brain but was abundant in rhesus monkey brain, suggesting that it is primate-specific. In various human brain tissues, KCNH2-3.1 transcript levels were markedly increased prenatally relative to adult levels, but appeared to decrease and stabilize shortly after birth. In contrast, KCNH2-1A expression increased throughout prenatal development until reaching a maximum level that was sustained throughout postnatal life. The findings suggested a specific role for KCNH2-3.1 during the early stages of human brain development. </p><p>Gianulis and Trudeau (2011) noted that full-length KCNH2 includes an N-terminal Per (see 602260)-Arnt (126110)-Sim (see 603128) (PAS) domain that regulates channel function. </p>
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</span>
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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>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Itoh et al. (1998) described the genomic organization of HERG. They found that the gene contains 15 exons spanning approximately 19 kb on chromosome 7q35. </p><p>By genomic sequence analysis, Splawski et al. (1998) determined that the HERG gene contains 16 exons (which included an alternative exon 1b), ranging from 100 bp to 553 bp. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR analysis of a somatic cell hybrid panel, Warmke and Ganetzky (1994) localized the KCNH2 gene to human chromosome 7. Curran et al. (1995) mapped the KCNH2 gene to chromosome 7q35-q36 by fluorescence in situ hybridization. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sanguinetti et al. (1995) expressed the HERG gene in Xenopus laevis oocytes and studied the potassium channel's biophysical properties and its sensitivity to various pharmacological agents. Their data indicated that HERG proteins form I(Kr) channels, but that another subunit may be required for certain drug sensitivities. Since block of I(Kr) is a known mechanism for drug-induced cardiac arrhythmias, their findings provided a mechanistic link between certain types of inherited and acquired long QT (LQT) syndrome. Acquired long QT syndrome occurs following treatment with certain medications and in association with reduced serum potassium levels (hypokalemia). Both acquired and inherited LQT are associated with torsade de pointes and polymorphic ventricular tachycardia resulting from abnormal cardiac depolarization (as detected by QT prolongation on the electrocardiogram). LQT is also characterized by sinusoidal twisting of the QRS axis around the isoelectric line. Torsade de pointes can degenerate into ventricular fibrillation, which can lead to sudden death. </p><p>Trudeau et al. (1995) likewise demonstrated that HERG encodes an inwardly rectifying potassium channel. Inward rectifiers are a large class of potassium channels that preferentially conduct inward potassium currents at voltages negative to the potassium equilibrium potential. In the heart, these channels also have small outward conductances that regulate the resting potential and contribute to the terminal phase of repolarization. At positive voltages, these channels close and thus help maintain the level of the resting potential. HERG channels show gating properties consistent with many of the outwardly rectifying potassium channels, but they also have an inactivation mechanism that attenuates efflux during depolarization. </p><p>The HERG potassium channel is unusual in that it seems to have the architectural plan of the depolarization-activated K+ channel family (6 putative transmembrane segments), yet it exhibits rectification like that of the inward-rectifying K+ channels, a family with different molecular structure (2 transmembrane segments). Smith et al. (1996) studied HERG channels expressed in mammalian cells and found that this inward rectification arises from a rapid and voltage-dependent inactivation process that reduces conductance at positive voltages. The inactivation gating mechanism resembles that of C-type inactivation, often considered to be the 'slow inactivation' mechanism of other K+ channels. Smith et al. (1996) noted that the characteristics of this gating suggested a specific role for this channel in the normal suppression of arrhythmias. They also commented that the role for HERG in suppressing extra beats might help explain the increased incidence of cardiac sudden death in patients that lack HERG currents, either because they carry a genetic defect (familial long QT syndrome type 2; LQT2; 613688) or because they are being treated with class III antiarrhythmics that block HERG channels. Miller (1996) commented on the discovery and its relation to heart disease. </p><p>Li et al. (1997) identified a subunit interaction domain, termed the NAB domain, in the hydrophilic cytoplasmic N terminus of HERG. This domain is responsible for the oligomerization of the protein into functional tetramers. </p><p>Ficker et al. (2003) demonstrated that the cytosolic chaperones HSP70 (140550) and HSP90 (140571) interact directly with the core-glycosylated form of wildtype HERG gene product present in the ER, but not the fully glycosylated, cell surface form. Trafficking-deficient mutants remained tightly associated with HSP70 and HSP90 in the ER, whereas a nonfunctional but trafficking HERG was released from the chaperones during maturation, comparable to the wildtype. Ficker et al. (2003) concluded that HSP90 and HSP70 are crucial for the maturation of wildtype HERG as well as the retention of trafficking-deficient LQT2 mutants. </p><p>Electrophysiologic studies in cultured cells by Huffaker et al. (2009) showed that KCNH2-3.1 mediated an inward rectified K(+) current with a high-frequency nonadapting firing pattern and markedly faster deactivation kinetics compared to KCNH2-1A. </p><p>Using patch-clamp recordings of transfected HEK293 cells, Gianulis and Trudeau (2011) showed that LQT2-associated amino acid substitutions on 1 face of the PAS domain of HERG altered channel gating. These substitutions accelerated channel deactivation kinetics, caused a positive rightward shift in the steady-state inactivation curve, and increased steady-state channel availability. Coexpression of the isolated, fluorescence-tagged PAS domain rescued the gating defect, presumably by supplanting the mutated PAS domain. Other substitutions within the PAS domain did not alter channel gating or resulted in no measurable currents. Gianulis and Trudeau (2011) concluded that the PAS domain regulates steady-state inactivation and activation properties of HERG channels. </p><p>Roder et al. (2014) found that overexpression of human RNF207 (616923) shortened action potential duration in neonatal rabbit ventricular cardiomyocytes. In human U2OS or HEK293 cell lines or rat cardiomyoblast H9c2 cells, overexpression of RNF207 increased membrane expression of cotransfected HERG. Elevated HERG membrane expression increased HERG tail current density, but it had no effect on other channel parameters. Mutation analysis revealed that HERG stability depended upon the RING finger domain of RNF207. RNF207 interacted with the core-glycosylated form of HERG, but not with the fully glycosylated form, in perinuclear regions, suggesting that they interact in the endoplasmic reticulum or cis-Golgi. The C terminus of RNF207 also interacted with the chaperone HSP70 (see 140550), and cotransfection of RNF207 with HSP70 had an additive effect on HERG stability. Expression of C-terminally truncated RNF207 had a dominant-negative effect on HERG stability. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Long QT Syndrome 2</em></strong></p><p>
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Curran et al. (1995) showed that the KCNH2 (HERG) gene mapped to the same YAC as D7S505, a polymorphic marker tightly linked to long QT syndrome-2 (LQT2; 613688). They found no recombination events using linkage analysis with polymorphisms within KCNH2 for linkage studies of chromosome 7-linked LQT. Using single-strand conformation polymorphism and DNA sequence analyses, Curran et al. (1995) detected HERG mutations in 6 LQT families, including 2 intragenic deletions, 1 splice-donor mutation, and 3 missense mutations. In 1 kindred, the mutation arose de novo. </p><p>Among 32 Japanese families with long QT syndrome, Tanaka et al. (1997) found that 5 families (9 patients) segregated mutant alleles of HERG. All were missense mutations and only 1, ala561-to-val (A561V; 152427.0001), had previously been reported. Satler et al. (1998) described 5 HERG mutations in 6 unrelated LQT kindreds. </p><p>Itoh et al. (1998) synthesized oligonucleotide primers to cover the entire coding region of HERG and searched for mutations in 36 Japanese families with long QT syndrome. They identified 5 novel mutations, using a combination of PCR/SSCP followed by direct DNA sequencing. </p><p>Zhou et al. (1998) used electrophysiologic, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT2 mutations. They found that some mutations, e.g., tyr611 to his (Y611H; 152427.0027) and val822 to met (152427.0005), caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum (ER). Other mutations, e.g., ile593 to arg (152427.0004) and gly628 to ser (152427.0008), were processed similarly to wildtype HERG protein, but these mutations did not produce functional channels. In contrast, the thr474-to-ile mutation expressed HERG current but with altered gating properties. These findings suggested that the loss of HERG channel function in LQT2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating. </p><p>In a large collaborative study, Zareba et al. (1998) determined the influence of genotype on phenotype of the long QT syndrome; 112 persons had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 (603830) locus. The frequency of cardiac events (syncope, aborted cardiac arrest, or sudden death) was highest with mutations at the LQT1 locus (63%) or the LQT2 locus (46%) than among subjects with mutations at the LQT3 locus (18%). The cumulative mortality through the age of 40 among members of 3 groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher among families with mutations at the LQT3 locus (20%) than among those with mutations at the LQT1 locus (4%) or the LQT2 locus (4%). </p><p>Priori et al. (1999) identified 9 families, each with a 'sporadic' case of LQTS, i.e., only the proband was diagnosed clinically as being affected by LQTS. Six probands were symptomatic for syncope, 2 were asymptomatic with QT prolongation found on routine examination, and 1 was asymptomatic but showed QT prolongation when examined following her brother's sudden death while swimming. Five had mutations in HERG (4 missense, 1 nonsense) and 4 had missense mutations in KCNQ1 (607542). Four of the mutations were de novo; in the remaining families at least 1 silent gene carrier was found, allowing estimation of penetrance at 25%. This contrasted greatly with the prevailing view that LQTS gene mutations may have penetrances of 90% or more. This study highlighted the importance of detecting such silent gene carriers since they are at risk of developing torsade de pointes if exposed to drugs that block potassium channels. Further, the authors stated, carrier status cannot be reliably excluded on clinical grounds alone. </p><p>In 2 severely affected sisters from a large Belgian family with long QT syndrome, Berthet et al. (1999) identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; 607542.0009) and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome. </p><p>Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2; SCN5A, 600163; KCNE1, 176261; KCNE2, 603796) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). </p><p>Moss et al. (2002) investigated the clinical features and prognostic implications of mutations involving the pore and nonpore regions of the HERG channel in LQT2. Forty-four different mutations in this gene were identified in 201 subjects, with 14 localized to the pore region (amino acid residues 550 through 650). A total of 35 individuals had mutations in the pore region and 166 in nonpore regions. Those with pore mutations had a markedly increased risk for arrhythmia-associated cardiac events (syncope, cardiac arrest, or sudden death) compared with those with nonpore mutations. </p><p>Yang et al. (2002) analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (607542.0031) and 1 in KCNH2 (152427.0014), not found in 228 controls, that were shown to reduce K+ currents in vitro. </p><p>Failure of cell surface expression because of defective HERG trafficking is known to cause LQT2 in some cases. Defective trafficking of membrane proteins results in a variety of other human diseases, as reviewed by Thomas et al. (1995). Membrane proteins are synthesized in the ER; misfolded and incompletely assembled proteins are common side products of ER protein synthesis, and a quality control mechanism recognizes such defects and results in their retention in the ER. If the defect cannot be corrected by an ER-associated chaperone, the protein is retrotranslocated to the cytosol and targeted for the degradative pathway. One ER retention signal is the amino acid triplet RXR, where 'X' can be any amino acid, although a large neutral or positively charged amino acid is preferred. Kupershmidt et al. (2002) identified an RXR motif in the C terminus of HERG which, when exposed by mutation, resulted in reduced cell surface trafficking. They studied the effect of a trp1001-to-ter (W1001X; 152427.0012) mutation, resulting in deletion of the C-terminal 159 amino acids of HERG (del159), with that of removal of the C-terminal 147 amino acids (del147). The 12 amino acids present in HERG-del147 and absent in HERG-del159 included the presumed ER retention signal RGR. </p><p>In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., 152427.0020 and 152427.0022-152427.0023). </p><p>In a Dutch family with long QT syndrome in which affected members carried an A558P mutation in the KCNH2 gene in heterozygosity (152427.0025), Amin et al. (2008) described fever-induced QT prolongation and demonstrated that the A558P mutation is trafficking-deficient, that it has a dominant-negative effect in coassembly with wildtype subunits, and that its current density fails to increase with increasing temperature to the same extent as wildtype channels. </p><p><strong><em>Short QT Syndrome 1</em></strong></p><p>
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In 2 families with short QT syndrome-1 (SQT1; 609620), previously reported by Gaita et al. (2003), Brugada et al. (2004) identified 2 different missense mutations in the KCNH2 gene (152427.0017 and 152427.0018, respectively), leading to the same asn588-to-lys (N588K) substitution. The mutation was present in all affected family members and in none of the unaffected individuals. Patch-clamp experiments revealed that the mutation dramatically increases I(Kr), leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduces the affinity of the channels to I(Kr) blockers. Hong et al. (2005) identified the N588K mutation in a third family with short QT syndrome, originally described by Gussak et al. (2000), and concluded that codon 588 is a hotspot for this familial form of the short QT syndrome. </p><p><strong><em>Susceptibility to Schizophrenia</em></strong></p><p>
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In a metaanalysis of 5 independent studies including a total of 1,158 patients with schizophrenia (181500) and 1,704 controls, Huffaker et al. (2009) found an association between the disorder and SNPs in intron 2 of the KCNH2 gene, in close proximity to the start site of the KCNH2-3.1 isoform. Control individuals with the at-risk SNPs showed lower IQ scores, decreased speed of cognitive processing, and altered memory-linked functional MRI signals, suggesting inefficient hippocampal activity, compared to controls without these SNPs. Patients with schizophrenia and those with the at-risk SNPs showed increased expression of the brain-specific isoform KCNH2-3.1 relative to KCNH2-1A compared to controls. Expression of KCNH2-1B, a minor isoform expressed within the brain, did not show significant differences between controls and patients with schizophrenia. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, 18 of whom were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. </p><p><strong><em>Reclassified Variants</em></strong></p><p>
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The I446V variant in the KCNH2 gene described by Yang et al. (2002) has been reclassified; see 152427.0014. Yang et al. (2002) analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (607542.0031) and 1 in KCNH2 (I446V; 152427.0014), not found in 228 controls, that were shown to reduce K+ currents in vitro. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Through homologous recombination in mouse embryonic stem cells, Lees-Miller et al. (2003) eliminated the ERG1 B potassium channel transcript while the ERG1 A transcript remained. Heterologous expression of ERG1 isoforms had previously indicated that the deactivation time course of ERG1 B is 10-fold more rapid than that of ERG1 A. In day 18 fetal +/+ myocytes, I(Kr) exhibited 2 time constants of deactivation, whereas in age-matched ERG1 B -/- mice the rapid component was absent. In adult ERG1 B -/- myocytes no I(Kr) was detected. Electrocardiogram intervals were similar in 6 of 21 +/+ and -/- mice; however, adult -/- mice manifested abrupt spontaneous episodes of sinus bradycardia This phenomenon was never observed in +/+ mice. Thus, ERG1 B appears to be necessary for I(Kr) expression in the surface membrane of adult myocytes. Lees-Miller et al. (2003) concluded that knockout of ERG1 B predisposes mice to episodic sinus bradycardia. </p><p>Rihel et al. (2010) reported the development and application of a high-throughput quantitative screen for drugs that alter the behavior of larval zebrafish. They found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. Rihel et al. (2010) found that ERG-blocking compounds specifically increased waking activity at night. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>A study by Xiao et al. (2007) in rabbits, suggesting that repression of ERG by miR133 (610254) likely underlies differential changes of ERG protein and transcript in diabetic hearts, results in reduced I(Kr) density, and contributes to QT prolongation and associated arrhythmias, was retracted. </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>27 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">
|
|
<strong>.0001 LONG QT SYNDROME 2</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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KCNH2, ALA561VAL
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<br />
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SNP: rs121912504,
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ClinVar: RCV000015501, RCV000057941, RCV000181806, RCV000229360, RCV000620827, RCV000626630, RCV003492296, RCV004562210
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of kindred with long QT syndrome showing linkage to chromosome 7 (LQT2; 613688), Curran et al. (1995) demonstrated an abnormal SSCP conformer that cosegregated with the disease. DNA sequence analyses of the normal and aberrant conformers demonstrated a C-to-T substitution at position 1682. This mutation resulted in substitution of valine for a highly conserved alanine residue at codon 561 (A561V). </p><p>To investigate mechanisms of dominant-negative behavior, Kagan et al. (2000) coexpressed wildtype HERG with the A561V mutant in mammalian cells. Transfection with various cDNA ratios produced HERG K+ current densities that approached a predicted binomial distribution where mutant and wildtype subunits coassembled in a tetramer with nearly complete dominance, and 1 subunit was sufficient to reduce functional activity nearly completely. Moreover, the mutant allele reduced the abundance of coexpressed wildtype HERG in cultured mammalian cells, both by decreasing synthesis of full-length protein and by increasing turnover. The effects exerted by the mutant protein were due, at least in part, to misfolding of assembling tetramers and targeting for early degradation, since conditions that facilitated proper folding or inhibitors of the proteasome partially reversed the effect. </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>.0002 LONG QT SYNDROME 2</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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KCNH2, ASN470ASP
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<br />
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SNP: rs121912505,
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ClinVar: RCV000015502, RCV000057902
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a kindred with long QT syndrome (LQT2; 613688), Curran et al. (1995) found that an aberrant SSCP conformer was due to an A-to-G substitution at position 1408, a mutation that resulted in substitution of aspartic acid for a conserved asparagine in the second transmembrane domain (N470D). </p><p>Gong et al. (2006) showed that both wildtype and mutant KCNH2 with the N470D substitution associated with the endoplasmic reticulum chaperone protein calnexin (CANX; 114217). However, the mutant protein showed prolonged association with calnexin, and like immature wildtype KCNH2, was more sensitive than mature wildtype KCNH2 to trypsin digestion. Gong et al. (2006) concluded that aberrant protein folding increases the association of mutant KCNH2 with calnexin and results in defective protein trafficking. </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>
|
|
<span class="mim-font">
|
|
<strong>.0003 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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KCNH2, IVS3DS, G-C, +1
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<br />
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|
|
SNP: rs794728391,
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|
|
ClinVar: RCV000015503, RCV000181858
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with sporadic long QT syndrome (LQT2; 613688), Curran et al. (1995) found that the cause of an aberrant HERG SSCP conformer was a G-to-C substitution converting GT to CT as the first 2 nucleotides of the splice donor sequence of intron 3. </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>.0004 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
KCNH2, ILE593ARG
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|
|
<br />
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|
|
SNP: rs28928904,
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|
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|
|
gnomAD: rs28928904,
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|
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ClinVar: RCV000015504, RCV000057986, RCV001545123, RCV001851874
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 members of 3 generations of a family with long QT syndrome-2 (LQT2; 613688), Benson et al. (1996) demonstrated a 1961T-G transversion in the HERG gene resulting in an ile593-to-arg amino acid substitution in the channel pore region. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, VAL822MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912506,
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|
|
|
|
|
|
|
ClinVar: RCV000015505, RCV000058125, RCV000254122, RCV000509399, RCV000806677, RCV001544763
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Satler et al. (1996) described a large Irish family with long QT syndrome. The disorder in this family was linked to chromosome 7q35-q36, establishing the phenotype as LQT2 (613688). SSCP analysis of the HERG gene showed a G-to-A change at position 2647 resulting in a substitution of methionine for valine at codon 822 and changing the cyclic nucleotide binding domain of the HERG protein. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, 27-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs794728438,
|
|
|
|
|
|
|
|
ClinVar: RCV000015506, RCV000181976, RCV003647757
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a kindred with long QT syndrome (LQT2; 613688), Curran et al. (1995) found that an aberrant SSCP conformer resulted from a 27-bp deletion at position 1500. This deletion causes an in-frame deletion of 9 amino acids in the third membrane-spanning domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, 1-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554426258,
|
|
|
|
|
|
|
|
ClinVar: RCV000015507, RCV005089262
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a kindred with long QT syndrome (LQT2; 613688), Curran et al. (1995) found that an aberrant SSCP conformer resulted from a 1-bp deletion at position 1261. This deletion causes a frameshift followed by a stop codon 12 amino acids downstream. </p><p>Li et al. (1997) found that truncated HERG proteins, including the deletion mutant at position 1261, contain the NAB domain, which is responsible for HERG oligomerization, but lack the rest of the channel and thus inhibit expression of functional tetrameric HERG channels in transfected cells. The authors suggested that LQT may be the result of decreased expression of a functional HERG potassium channel in the heart. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, GLY628SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912507,
|
|
|
|
|
|
|
|
ClinVar: RCV000015508, RCV000058029, RCV000223848, RCV000822422, RCV002408467, RCV004549371, RCV004558262
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with sporadic long QT syndrome (LQT2; 613688), Curran et al. (1995) found that the cause of an aberrant HERG SSCP conformer was a G-to-A substitution at position 1882 converting glycine-628 to serine. This amino acid residue is known to be critical for potassium ion selectivity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ARG582CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912508,
|
|
|
|
|
|
|
|
ClinVar: RCV000015509, RCV000057970, RCV000181815, RCV000537059, RCV002399326
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 Dutch families with long QT syndrome-2 (LQT2; 613688), Jongbloed et al. (1999) identified an arg582-to-cys mutation in the KCNH2 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, GLY572ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs9333649,
|
|
|
|
|
|
gnomAD: rs9333649,
|
|
|
|
|
|
ClinVar: RCV000015510, RCV000057960
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Larsen et al. (2000) reported a 4-generation family with long QT syndrome (LQT2; 613688) in which affected members had syncopes and torsade de pointes ventricular tachycardia elicited by abrupt awakening in the early morning hours. The authors identified a gly572-to-arg (G572R) missense mutation at the end of the S5 transmembrane segment of the HERG K+ channel in affected family members. Electrocardiograms (ECGs) of affected persons showed prolonged QT interval and notched T waves. Despite treatment with atenolol, 200 mg twice daily, the proband still experienced torsade de pointes ventricular tachycardia. Three untreated relatives had died suddenly and unexpectedly at 18, 32, and 57 years of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LONG QT SYNDROME, BRADYCARDIA-INDUCED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ALA490THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28928905,
|
|
|
|
|
|
|
|
ClinVar: RCV000015511, RCV000057910, RCV000182022, RCV000703745, RCV000709729, RCV002390110
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Yoshida et al. (2001) reported a 27-year-old patient with bradycardia-induced long QT syndrome (LQT2; 613688) with a de novo HERG mutation. A 1468G-A substitution in exon 6 of the KCNH2 gene resulted in an ala490-to-thr (A490T) mutation in the S2-S3 inner loop of HERG. The authors suggested that this mutation may cause subtle changes in HERG channel functions in vivo. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, TRP1001TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912509,
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|
|
|
|
|
gnomAD: rs121912509,
|
|
|
|
|
|
ClinVar: RCV000015512, RCV000181905, RCV001207958
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kupershmidt et al. (2002) studied the pathogenetic mechanisms involved in long QT syndrome (LQT2; 613688) in a family with a transition mutation at nucleotide 3003 of the HERG gene, converting codon 1001 from TGG (trp) to TGA (ter). They concluded that the C terminus of HERG contains an RXR motif which, when exposed by mutation, results in reduced cell surface trafficking. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, SER818LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912510,
|
|
|
|
|
|
gnomAD: rs121912510,
|
|
|
|
|
|
ClinVar: RCV000015513, RCV000058123, RCV000631649, RCV002426506, RCV003591634, RCV004696637
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Berthet et al. (1999) identified a ser818-to-leu (S818L) mutation, located in the putative cyclic nucleotide binding domain in the HERG C terminus, in patients with long QT syndrome (LQT2; 613688). Nakajima et al. (2000) found the same mutation in Japanese LQT2 patients and examined the mechanism for HERG channel dysfunction, using the heterologous expression system in Xenopus oocytes. The data suggested that S818L alone cannot form functional channels, whereas S818L subunits can, at least in part, coassemble with wildtype subunits to form heterotetrameric functional channels. The data also implied that the HERG C terminus may contain a domain involving the activation-deactivation process of the channel. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNH2, ARG784TRP
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<br />
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|
|
SNP: rs12720441,
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|
|
gnomAD: rs12720441,
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|
ClinVar: RCV000058108, RCV000208497, RCV001262685, RCV001841245, RCV001851875, RCV002223758, RCV003162252, RCV004549372, RCV004720231
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>This variant, formerly titled LONG QT SYNDROME 2, ACQUIRED, SUSCEPTIBILITY TO, has been reclassified based on the article by Lacaze et al. (2021). </p><p>Yang et al. (2002) described an individual who developed QT prolongation and torsade de pointes while taking the drug amiodarone (see 613688). The ECG abnormalities reversed on drug withdrawal. Analysis of the coding sequence of the gene encoding HERG revealed a C-to-T transition at nucleotide position 2350, which resulted in an arginine-to-tryptophan substitution at amino acid position 784 (R784W). The mutation was not found in 228 controls. In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents. These findings suggested that the R784W mutation was responsible for the patient's response to amiodarone. </p><p>In a review of genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults (mean age, 75 years) of European descent, Lacaze et al. (2021) identified the R784W variant in 3 alleles, thus calling its pathogenicity into question. </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 LONG QT SYNDROME 2</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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KCNH2, THR65PRO
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<br />
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SNP: rs121912511,
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ClinVar: RCV000015515, RCV000058063
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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 patient with long QT syndrome (LQT2; 613688), Paulussen et al. (2002) identified and characterized a novel 193A-C transversion in exon 2 of the PAS domain of the HERG gene causing a thr65-to-pro (T65P) substitution and resulting in defective trafficking of the protein to the cell membrane. Defective folding of the mutant protein could be restored by decreased cell incubation temperature and pharmacologically. When trafficking was restored by growing cells at 27 degrees C, the kinetics of the mutated channel resembled that of wildtype channels although the rates of activation, deactivation, and recovery from inactivation were accelerated. No positive evidence for the formation of heterotetramers was obtained by coexpression of wildtype with mutant subunits at 37 degrees C. As a consequence, the clinical symptoms may be explained by haploinsufficiency rather than by dominant-negative effects. Paulussen et al. (2002) stated that 6 trafficking-deficient mutations had previously been described in the HERG gene and that this study was the first to relate a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation. </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>
|
|
<span class="mim-font">
|
|
<strong>.0016 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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KCNH2, ARG752GLN
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<br />
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SNP: rs121912512,
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|
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gnomAD: rs121912512,
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|
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ClinVar: RCV000015516, RCV000058100, RCV000148536, RCV001659699
|
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|
|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
<p>In an infant with long QT syndrome (LQT2; 613688) who was initially referred at 38 weeks' gestation for irregular heartbeat, Johnson et al. (2003) found a homozygous G-to-A transition at nucleotide 2255 of the HERG gene resulting in an arg752-to-gln (R752Q) substitution. The heterozygous mother and maternal aunt and grandmother had normal ECGs and were asymptomatic, and there was no family history suggestive of LQTS. Maternal isodisomy was excluded. The absent father was said to be healthy. All 4 individuals with the R752Q mutation also had the G643S HERG polymorphism (Itoh et al., 1998). </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>
|
|
<span class="mim-font">
|
|
<strong>.0017 SHORT QT SYNDROME 1</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
KCNH2, ASN588LYS, 1764C-G
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|
<br />
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|
|
SNP: rs104894021,
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|
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ClinVar: RCV000015517, RCV000057981, RCV004991976
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|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with short QT syndrome-1 (SQT1; 609620), previously reported by Gaita et al. (2003), Brugada et al. (2004) identified respective 1764C-G and 1764C-A (152427.0018) transversions in exon 7 of the KCNH2 gene, leading to the same asn588-to-lys (N588K) substitution in the S5-P loop region of the cardiac I(Kr) channel. The mutation was present in all affected family members and in none of the unaffected individuals. </p><p>In a family with short QT syndrome, originally reported by Gussak et al. (2000), Hong et al. (2005) identified the 1764C-G transversion in the KCNH2 gene and concluded that N588K is a hotspot for this familial form of short QT syndrome. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
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|
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<div>
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|
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 SHORT QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ASN588LYS, 1764C-A
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs104894021,
|
|
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|
|
|
|
ClinVar: RCV000015518, RCV000057980, RCV004991977
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with short QT syndrome-1 (SQT1; 609620), previously reported by Gaita et al. (2003), Brugada et al. (2004) identified respective 1764C-G (152427.0017) and 1764C-A transversions in exon 7 of the KCNH2 gene, leading to the same asn588-to-lys (N588K) substitution in the S5-P loop region of the cardiac I(Kr) channel. The mutation was present in all affected family members and in none of the unaffected individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 LONG QT SYNDROME 1/2, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, IVS10, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554424772,
|
|
|
|
|
|
|
|
ClinVar: RCV000015519, RCV003531902, RCV004719649
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 severely affected sisters from a large Belgian family with long QT syndrome (see 613688), Berthet et al. (1999) identified biallelic digenic mutations: a +1G-A transition at the donor splice site in IVS10 of the KCNH2 gene (2592+1G-A), and an A341E substitution in the KCNQ1 gene (607542.0009). The father and his affected relatives were heterozygous for the A341E mutation in KCNQ1; the mother, a more mildly affected sister, and a grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected family members, and the KCNH2 splice site mutation was not found in more than 100 unrelated controls. Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 1/2, DIGENIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, 1-BP INS, 2775G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs794728455,
|
|
|
|
|
|
gnomAD: rs794728455,
|
|
|
|
|
|
ClinVar: RCV000015520, RCV000015521, RCV000181993, RCV000204205, RCV000249424, RCV001842847
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with long QT syndrome (LQT2; 613688), Splawski et al. (2000) identified heterozygosity for a 1-bp insertion (2775insG) in exon 12 of the KCNH2 gene, causing a frameshift at pro926 that results in a termination signal 13 codons downstream. </p><p>In a female infant with a family history of sudden death, who had severe, continuous bradycardia in utero that was confirmed after birth and a QTc of 485 ms, Millat et al. (2006) identified biallelic digenic mutations: 2775insG in the KCNH2 gene and a deletion in the KCNQ1 gene (562delT; 607542.0038). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 2/5, DIGENIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ASN861ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912513,
|
|
|
|
|
|
|
|
ClinVar: RCV000015522, RCV000015523, RCV000058141, RCV002223759, RCV002490375, RCV003531903
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with long QT syndrome (LQT2; 613688), Splawski et al. (2000) identified heterozygosity for a 2582A-T transversion in exon 10 of the KCNH2 gene, resulting in an asn861-to-ile (N861I) substitution. </p><p>In a female patient who had a QTc of 460 ms and suffered cardiac arrest, Westenskow et al. (2004) identified triallelic digenic mutations: heterozygosity for an N861I substitution in the KCNH2 gene and homozygosity for a missense mutation in the KCNE1 gene (D85N; 176261.0005). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 LONG QT SYNDROME 1/2, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ARG948CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912514,
|
|
|
|
|
|
gnomAD: rs121912514,
|
|
|
|
|
|
ClinVar: RCV000015524, RCV000058169, RCV001318613, RCV001794448, RCV001841246, RCV002496372
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female infant with fetal and neonatal bradycardia and a QTc of 570 ms (see 613688), Millat et al. (2006) identified biallelic digenic mutations: a 2841C-T transition in exon 12 of the KCNH2 gene, resulting in an arg948-to-cys (R948C) substitution, and a missense mutation in the KCNQ1 gene (R243P; 607542.0039). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 LONG QT SYNDROME 2/3, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ARG100GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912515,
|
|
|
|
|
|
gnomAD: rs121912515,
|
|
|
|
|
|
ClinVar: RCV000015525, RCV000058186, RCV000181948, RCV000617723, RCV002247344
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 41-year-old female who had cardiac arrest due to torsade de pointes triggered by exercise and leading to ventricular fibrillation, and a QTc of 520 ms (see 613688), Millat et al. (2006) identified biallelic digenic mutations: a 298C-G transversion in exon 2 of the KCNH2 gene, resulting in an arg100-to-gly (R100G) substitution, and a missense mutation in the SCN5A gene (D1819N; 600163.0035). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 2/9, DIGENIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ARG913VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs77331749,
|
|
|
|
|
|
gnomAD: rs77331749,
|
|
|
|
|
|
ClinVar: RCV000015526, RCV000015527, RCV000058156, RCV000204621, RCV000589886, RCV000620709, RCV001841247
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with long QT syndrome (LQT2; 613688), Tester et al. (2005) identified a 2738C-T transition in exon 12 of the KCNH2 gene, resulting in an ala913-to-val (A913V) substitution in the C terminus. </p><p>In a 14-year-old girl with long QT syndrome (see 613688), Vatta et al. (2006) identified biallelic digenic mutations: the A913V mutation in the KCNH2 gene and a T78M mutation in the LQT9-associated CAV3 gene (601253.0018). The patient had nonexertional syncope and a 'seizure-like' presentation, with U waves, sinus bradycardia, and a QTc of 405 ms on ECG; she had a positive family history, but family members declined further genotyping. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 LONG QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNH2, ALA558PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912516,
|
|
|
|
|
|
|
|
ClinVar: RCV000015528, RCV000057935
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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<p>In a 3-generation Dutch family with long QT syndrome (LQT2; 613688), Jongbloed et al. (1999) identified heterozygosity for a 1672G-C transversion in exon 7 of the KCNH2 gene, resulting in an ala558-to-pro (A558P) substitution. The index patient was a 22-year-old woman who had died suddenly upon arousal from sleep by an alarm clock. </p><p>Amin et al. (2008) reported that the father and brother of the index patient described by Jongbloed et al. (1999), both carriers of the A558P mutation, suffered repeated occurrences of fever-induced syncope, polymorphic ventricular tachycardia, and ventricular fibrillation. Electrocardiography showed increased QTc with fever in both patients. Studies in HEK293 cells showed that the A558P protein has a trafficking-deficient phenotype. Coexpression of A558P and wildtype proteins demonstrated a dominant-negative effect of the mutation, a selectively accelerated rate of channel inactivation, and reduced temperature-dependent increase in the wildtype current. Amin et al. (2008) suggested that the weak increase in HERG current density in wildtype-mutant coassembled channels contributed to the development of QTc prolongation and arrhythmias at febrile temperatures. </p>
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</span>
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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>.0026 LONG QT SYNDROME 2</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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KCNH2, ALA614VAL
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<br />
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SNP: rs199472944,
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ClinVar: RCV000022643, RCV000058010, RCV000254785, RCV000462085, RCV002408476
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</span>
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</div>
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<span class="mim-text-font">
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<p>Tanaka et al. (1997) identified a C-to-T transition in exon 9 of the KCNH2 gene resulting in an alanine-to-valine substitution at codon 614 (A614V) in a member of a cohort of Japanese patients with long QT syndrome (LQT2; 613688). This same mutation was identified in an Israeli family with long QT syndrome by Tenenbaum et al. (2008). </p><p>Itzhaki et al. (2011) developed a patient/disease-specific human induced pluripotent stem cell (iPSC) line from a patient with LQT2 due to an A614V missense mutation in the KCNH2 gene. The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action potential duration in LQTS human iPSC-derived cardiomyocytes when compared to healthy control cells. Voltage-clamp studies confirmed that this action potential duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. Itzhaki et al. (2011) then used the LQTS human iPSC-derived cardiac tissue model to evaluate the potency of existing and novel pharmacologic agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers, and late sodium-channel blockers) the disease phenotype. Itzhaki et al. (2011) concluded that their study illustrated the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0027 LONG QT SYNDROME 2</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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KCNH2, TYR611HIS
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<br />
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SNP: rs199472942,
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ClinVar: RCV000022644, RCV000058006
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a Japanese family with long QT syndrome (LQT2; 613688), Tanaka et al. (1997) identified a T-to-C transition in the KCNH2 gene, resulting in a tyr611-to-his (Y611H) substitution between the S5 and pore regions of the protein. </p><p>Zhou et al. (1998) found that the Y611H mutation in KCNH2 resulted in defective biosynthetic processing, with the protein retained in the endoplasmic reticulum. </p><p>Gong et al. (2005) found that KCNH2 with the Y611H mutation was deglycosylated, ubiquitinated, and degraded via the proteasome. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<li>
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<strong>Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.</strong>
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<strong>Defective human ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus.</strong>
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Lacaze, P., Sebra, R., Riaz, M., Ingles, J., Tiller, J., Thompson, B. A., James, P. A., Fatkin, D., Semsarian, C., Reid, C. M., Tonkin, A. M., Winship, I., Schadt, E., McNeil, J. J.
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<strong>Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.</strong>
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NPJ Genomic Med. 6: 51, 2021.
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<p class="mim-text-font">
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Larsen, L. A., Svendsen, I. H., Jensen, A. M., Kanters, J. K., Andersen, P. S., Moller, M., Sorensen, S. A., Sandoe, E., Jacobsen, J. R., Vuust, J., Christiansen, M.
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<strong>Long QT syndrome with a high mortality rate caused by a novel G572R missense mutation in KCNH2.</strong>
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[PubMed: 10735633]
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<p class="mim-text-font">
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Lees-Miller, J. P., Guo, J., Somers, J. R., Roach, D. E., Sheldon, R. S., Rancourt, D. E., Duff, H. J.
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<strong>Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia.</strong>
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[PubMed: 12612061]
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<li>
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<p class="mim-text-font">
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Li, X., Xu, J., Li, M.
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<strong>The human delta-1261 mutation of the HERG potassium channel results in a truncated protein that contains a subunit interaction domain and decreases the channel expression.</strong>
|
|
J. Biol. Chem. 272: 705-708, 1997.
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[PubMed: 8995352]
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[Full Text: https://doi.org/10.1074/jbc.272.2.705]
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Contributors:
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 4/26/2016<br>Marla J. F. O'Neill - updated : 3/25/2016<br>Marla J. F. O'Neill - updated : 3/28/2014<br>Matthew B. Gross - updated : 1/17/2012<br>Patricia A. Hartz - updated : 10/6/2011<br>Ada Hamosh - updated : 6/14/2011<br>Ada Hamosh - updated : 2/1/2010<br>Cassandra L. Kniffin - updated : 5/21/2009<br>Marla J. F. O'Neill - updated : 12/19/2008<br>Marla J. F. O'Neill - updated : 11/21/2008<br>Marla J. F. O'Neill - updated : 2/12/2008<br>Victor A. McKusick - updated : 2/26/2007<br>Marla J. F. O'Neill - updated : 12/8/2006<br>Marla J. F. O'Neill - updated : 11/9/2006<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Victor A. McKusick - updated : 10/7/2004<br>Marla J. F. O'Neill - updated : 3/3/2004<br>Natalie E. Krasikov - updated : 12/19/2003<br>Victor A. McKusick - updated : 5/2/2003<br>Victor A. McKusick - updated : 2/12/2003<br>Paul Brennan - updated : 12/4/2002<br>Paul Brennan - updated : 12/4/2002<br>Victor A. McKusick - updated : 9/25/2002<br>Paul Brennan - updated : 8/7/2002<br>Paul Brennan - updated : 3/14/2002<br>Sonja A. Rasmussen - updated : 3/13/2001<br>Paul J. Converse - updated : 5/23/2000<br>Victor A. McKusick - updated : 4/21/2000<br>Paul Brennan - updated : 4/7/2000<br>Victor A. McKusick - updated : 6/3/1999<br>Victor A. McKusick - updated : 10/2/1998<br>Victor A. McKusick - updated : 9/14/1998<br>Clair A. Francomano - updated : 5/27/1998<br>Victor A. McKusick - updated : 11/17/1997<br>Alan F. Scott - updated : 9/17/1995
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Victor A. McKusick : 9/16/1993
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