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Entry
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- *605206 - HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL 4; HCN4
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605206</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605206">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li 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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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000138622;t=ENST00000261917" 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=10021" 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=605206" 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=ENSG00000138622;t=ENST00000261917" 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_005477,XM_011521148" 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_005477" 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=605206" 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=09240&isoform_id=09240_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/HCN4" 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/4775353,4885407,5734516,38605641,119598331,371511131,767983093,2462542499" 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/Q9Y3Q4" 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=10021" 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=ENSG00000138622;t=ENST00000261917" 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=HCN4" 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=HCN4" 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+10021" 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/HCN4" 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:10021" 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/10021" 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=chr15&hgg_gene=ENST00000261917.4&hgg_start=73319859&hgg_end=73368958&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:16882" 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/hcn4" 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=605206[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605206[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/HCN4/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/ENSG00000138622" 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=HCN4" 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=HCN4" 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=HCN4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HCN4&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/PA394" 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:16882" 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/FBgn0263397.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:1298209" 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/HCN4#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:1298209" 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/10021/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=10021" 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://zfin.org/ZDB-GENE-050420-360" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10021" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=HCN4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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605206
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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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HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL 4; HCN4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<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=HCN4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HCN4</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/15/361?start=-3&limit=10&highlight=361">15q24.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:73319859-73368958&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'})">15:73,319,859-73,368,958</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=619521,613123,163800" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
|
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<span class="mim-font">
|
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<a href="/geneMap/15/361?start=-3&limit=10&highlight=361">
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15q24.1
|
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</a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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{Epilepsy, idiopathic generalized, susceptibility to, 18}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/619521"> 619521 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Brugada syndrome 8
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/613123"> 613123 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Sick sinus 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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<a href="/entry/163800"> 163800 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
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<p>The HCN4 gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated ion channel family, which are expressed at the cell membrane and contribute to the resting membrane potential. HCN4 is expressed in the heart and in several brain regions, including the thalamus (summary by <a href="#2" class="mim-tip-reference" title="Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D. <strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong> Front. Molec. Neurosci. 11: 269, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30127718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30127718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30127718[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/10.3389/fnmol.2018.00269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30127718">Campostrini et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30127718" 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>Cardiac pacemaking is produced by the slow diastolic depolarization phase of the action potential. The hyperpolarization-activated cation current forms an important part of the pacemaker depolarization and consists of 2 kinetic components, fast and slow. To elucidate the molecular identity of cardiac pacemaking channels, <a href="#6" class="mim-tip-reference" title="Ludwig, A., Zong, X., Stieber, J., Hullin, R., Hofmann, F., Biel, M. <strong>Two pacemaker channels from human heart with profoundly different activation kinetics.</strong> EMBO J. 18: 2323-2329, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10228147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10228147</a>] [<a href="https://doi.org/10.1093/emboj/18.9.2323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10228147">Ludwig et al. (1999)</a> screened a human heart cDNA library with a probe corresponding to a highly conserved portion of the mouse HCN1 (<a href="/entry/602780">602780</a>) channel and identified 2 cDNAs, HCN2 (<a href="/entry/602781">602781</a>) and HCN4. The HCN4 cDNA predicts a protein of 1,203 amino acids. HCN4 contains 6 putative transmembrane segments, a pore region, and a cyclic nucleotide-binding domain (CNBD). Northern blot and PCR analyses showed that HCN4 is expressed at heart ventricle and atrium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10228147" 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="Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B. <strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong> Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.16.9391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10430953">Seifert et al. (1999)</a> independently cloned HCN4. Northern blot analysis showed the HCN4 transcripts were expressed in heart, brain, and testis. Within the brain, the thalamus is the predominant area of HCN4 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10430953" 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 in situ hybridization and immunohistochemical analysis of mouse embryos at embryonic day 10.5, <a href="#15" class="mim-tip-reference" title="Stieber, J., Herrmann, S., Feil, S., Loster, J., Feil, R., Biel, M., Hofmann, F., Ludwig, A. <strong>The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in embryonic heart.</strong> Proc. Nat. Acad. Sci. 100: 15235-15240, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14657344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.2434235100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14657344">Stieber et al. (2003)</a> detected high levels of Hcn4 mRNA and protein in developing embryonic cardiac regions, including the walls of the common cardinal veins entering the sinus venosa. Much lower expression was detected in the developing central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14657344" 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="#10" class="mim-tip-reference" title="Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D. <strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong> J. Clin. Invest. 111: 1537-1545, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[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/JCI16387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750403">Schulze-Bahr et al. (2003)</a> determined that the HCN4 gene contains 8 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750403" 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="#13" class="mim-tip-reference" title="Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B. <strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong> Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.16.9391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10430953">Seifert et al. (1999)</a> mapped the HCN4 gene to chromosome band 15q24-q25 by FISH. By genomic sequence analysis, <a href="#10" class="mim-tip-reference" title="Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D. <strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong> J. Clin. Invest. 111: 1537-1545, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[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/JCI16387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750403">Schulze-Bahr et al. (2003)</a> mapped the HCN4 gene to chromosome 15q23-q24.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12750403+10430953" 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="#6" class="mim-tip-reference" title="Ludwig, A., Zong, X., Stieber, J., Hullin, R., Hofmann, F., Biel, M. <strong>Two pacemaker channels from human heart with profoundly different activation kinetics.</strong> EMBO J. 18: 2323-2329, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10228147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10228147</a>] [<a href="https://doi.org/10.1093/emboj/18.9.2323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10228147">Ludwig et al. (1999)</a> expressed HCN4 in HEK293 cells and observed that HCN4 gives rise to hyperpolarization-activated cation currents with the hallmark features of the native cation current. HCN4 currents differ profoundly from HCN2 currents in their activation kinetics, being slow and fast, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10228147" 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="Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B. <strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong> Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.16.9391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10430953">Seifert et al. (1999)</a> demonstrated that heterologous expression of HCN4 produced channels of unusually slow kinetics of activation and inactivation. The mean potential of half-maximal activation was -75.2 mV. The characteristic expression pattern and the sluggish gating suggested to <a href="#13" class="mim-tip-reference" title="Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B. <strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong> Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.16.9391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10430953">Seifert et al. (1999)</a> that HCN4 controls the rhythmic activity in both thalamocortical neurons and pacemaker cells of the heart. The strong hybridization with testis mRNA further suggested to <a href="#13" class="mim-tip-reference" title="Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B. <strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong> Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.16.9391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10430953">Seifert et al. (1999)</a> that HCN4 is also expressed in mature spermatozoa or their precursor cells. In this respect, HCN4 may represent the mammalian equivalent of the HCN channel in the flagellum of sea urchin spermatozoa (<a href="#4" class="mim-tip-reference" title="Gauss, R., Seifert, R., Kaupp, U. B. <strong>Molecular identification of a hyperpolarization-activated channel in sea urchin sperm.</strong> Nature 393: 583-587, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634235</a>] [<a href="https://doi.org/10.1038/31248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634235">Gauss et al., 1998</a>). <a href="#13" class="mim-tip-reference" title="Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B. <strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong> Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.16.9391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10430953">Seifert et al. (1999)</a> proposed that both the sea urchin channel and the human HCN4 may be involved in the generation of rhythmic activity that controls the waveform of flagellar beating. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9634235+10430953" 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>Sour taste is initiated by protons acting at receptor proteins or channels. <a href="#14" class="mim-tip-reference" title="Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U. B., Lindemann, B. <strong>Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.</strong> Nature 413: 631-635, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675786</a>] [<a href="https://doi.org/10.1038/35098087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675786">Stevens et al. (2001)</a> examined the effects of sour stimuli on taste cells in slices of vallate papilla from rat. From a subset of cells, <a href="#14" class="mim-tip-reference" title="Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U. B., Lindemann, B. <strong>Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.</strong> Nature 413: 631-635, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675786</a>] [<a href="https://doi.org/10.1038/35098087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675786">Stevens et al. (2001)</a> identified a hyperpolarization-activated current that was enhanced by sour stimulation at the taste pore. This current resembled I(h) found in neurons and cardiomyocytes, a current carried by members of the family of hyperpolarization-activated and cyclic-nucleotide-gated (HCN) channels. <a href="#14" class="mim-tip-reference" title="Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U. B., Lindemann, B. <strong>Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.</strong> Nature 413: 631-635, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675786</a>] [<a href="https://doi.org/10.1038/35098087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675786">Stevens et al. (2001)</a> showed by in situ hybridization and immunohistochemistry that HCN1 and HCN4 are expressed in a subset of taste cells. By contrast, gustducin (<a href="/entry/139395">139395</a>), the G protein involved in bitter and sweet taste, was not expressed in these cells. <a href="#14" class="mim-tip-reference" title="Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U. B., Lindemann, B. <strong>Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.</strong> Nature 413: 631-635, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675786</a>] [<a href="https://doi.org/10.1038/35098087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675786">Stevens et al. (2001)</a> concluded that HCN channels are gated by extracellular protons and may act as receptors for sour taste. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11675786" 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>Sick Sinus Syndrome 2</em></strong></p><p>
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In a 66-year-old woman with symptomatic sinus bradycardia (SSS2; <a href="/entry/163800">163800</a>), <a href="#10" class="mim-tip-reference" title="Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D. <strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong> J. Clin. Invest. 111: 1537-1545, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[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/JCI16387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750403">Schulze-Bahr et al. (2003)</a> identified heterozygosity for a 1-bp deletion (<a href="#0002">605206.0002</a>) in the HCN4 gene that was not found in 362 control chromosomes. Patch-clamp experiments in COS-7 cells demonstrated that the mutant channels mediated I(f) currents that were insensitive to increased cellular cAMP levels; coexpression studies showed a dominant-negative effect of the mutant subunits on wildtype subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A. <strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong> J. Biol. Chem. 279: 27194-27198, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123648</a>] [<a href="https://doi.org/10.1074/jbc.M311953200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15123648">Ueda et al. (2004)</a> analyzed the HCN4 gene in 6 patients with sinus node dysfunction, 3 patients with progressive cardiac conduction disturbances, and 14 patients with idiopathic ventricular fibrillation, all of whom were negative for mutations in 6 known ion channel genes, and identified heterozygosity for a mutation in 1 proband with sinus node dysfunction (D553N; <a href="#0003">605206.0003</a>). The mutation was also found in the proband's affected sister and son, and was not present in 380 control chromosomes. In vitro analysis showed reduced membrane expression associated with decreased I(f) currents because of a trafficking defect of the HCN4 channel in a dominant-negative fashion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123648" 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="#7" class="mim-tip-reference" title="Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D. <strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong> New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407510</a>] [<a href="https://doi.org/10.1056/NEJMoa052475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407510">Milanesi et al. (2006)</a> found that sinus bradycardia was associated with a mutation (<a href="#0001">605206.0001</a>) in the gene encoding the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cAMP-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis showed that mutant channels respond normally to cAMP but are activated at more negative voltages than are wildtype channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407510" 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 8 affected members of a 4-generation family with asymptomatic sinus bradycardia, <a href="#9" class="mim-tip-reference" title="Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M. <strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong> Circulation 116: 463-470, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646576</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.706887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646576">Nof et al. (2007)</a> identified a heterozygous mutation in the HCN4 gene (G480R; <a href="#0004">605206.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646576" 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 4-generation German family with sinus bradycardia, biventricular hypertrabeculation, and mitral valve prolapse (MVP), <a href="#11" class="mim-tip-reference" title="Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M. <strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong> Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>] [<a href="https://doi.org/10.1161/CIRCEP.110.949768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20693575">Schweizer et al. (2010)</a> identified heterozygosity for a 13-bp insertion in the HCN4 gene (<a href="#0007">605206.0007</a>) that segregated fully with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20693575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large Dutch family with bradycardia, left ventricular noncompaction (LVNC), and MVP, <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> identified heterozygosity for a missense mutation in the HCN4 gene (G482R; <a href="#0008">605206.0008</a>). Analysis of HCN4 in 3 families with a similar phenotype revealed heterozygosity for a Y481H mutation (<a href="#0009">605206.0009</a>) in 2 of them, and an A414G mutation (<a href="#0010">605206.0010</a>) in the third. The mutations segregated with disease in each family and were not found in controls or in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145517" 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 German mother and 2 children with sinus node dysfunction, LVNC, and MVP, <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> identified heterozygosity for the G482R mutation in the HCN4 gene. In addition, the mother was homozygous and the 2 children heterozygous for a variant of unknown significance in the CSRP3 gene (W4R; see <a href="/entry/600824#0001">600824.0001</a>); the authors stated that this variant was unlikely to be a primary cause of the cardiac noncompaction phenotype, but suggested that it might make a modifying contribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145518" 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 sinus bradycardia, LVNC, MVP, and dilation of the ascending aorta, <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> identified the Y481H mutation in the HCN4 gene. <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reviewed multimodal imaging studies available from previously described patients with HCN4 mutations (<a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al., 2014</a>; <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al., 2014</a>) and detected dilation of the ascending aorta in 13 of 18 patients with adequate studies, for an overall detection rate of 77% in HCN4 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25145518+27173043+25145517" 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>Brugada Syndrome 8</em></strong></p><p>
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In a 41-year-old man with Brugada syndrome-8 (BRGDA8; <a href="/entry/613123">613123</a>) who was negative for mutation in the SCN5A gene (<a href="/entry/600163">600163</a>), <a href="#16" class="mim-tip-reference" title="Ueda, K., Hirano, Y., Higashiuesato, Y., Aizawa, Y., Hayashi, T., Inagaki, N., Tana, T., Ohya, Y., Takishita, S., Muratani, H., Hiraoka, M., Kimura, A. <strong>Role of HCN4 channel in preventing ventricular arrhythmia.</strong> J. Hum. Genet. 54: 115-121, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165230</a>] [<a href="https://doi.org/10.1038/jhg.2008.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19165230">Ueda et al. (2009)</a> identified heterozygosity for a splice site mutation in the HCN4 gene (<a href="#0005">605206.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165230" 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 Idiopathic Generalized Epilepsy 18</em></strong></p><p>
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In 2 brothers with idiopathic generalized epilepsy-18 (EIG18; <a href="/entry/619521">619521</a>), <a href="#2" class="mim-tip-reference" title="Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D. <strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong> Front. Molec. Neurosci. 11: 269, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30127718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30127718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30127718[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/10.3389/fnmol.2018.00269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30127718">Campostrini et al. (2018)</a> identified a heterozygous missense mutation in the HCN4 gene (R550C; <a href="#0011">605206.0011</a>). Electrophysiologic studies in CHO cells showed that the mutation caused a negative shift in the activation curve compared to wildtype, consistent with a loss of channel function. Neuronal hyperexcitability and increased firing was observed in neuronal cells transfected with the mutation, which exerted a dominant effect when coexpressed with wildtype. <a href="#2" class="mim-tip-reference" title="Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D. <strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong> Front. Molec. Neurosci. 11: 269, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30127718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30127718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30127718[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/10.3389/fnmol.2018.00269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30127718">Campostrini et al. (2018)</a> concluded that reduced HCN4 current contribution may affect input membrane resistance and resting membrane potential, causing cell hyperexcitability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30127718" 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="Becker, F., Reid, C. A., Hallmann, K., Tae, H.-S., Phillips, A. M., Teodorescu, G., Weber, Y. G., Kleefuss-Lie, A., Elger, C., Perez-Reyes, E., Petrou, S., Kunz, WS., Lerche, H., Maljevic, S. <strong>Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy.</strong> Epilepsia Open 2: 334-342, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29588962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29588962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29588962[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/10.1002/epi4.12068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29588962">Becker et al. (2017)</a> identified a heterozygous missense variant (E153G) in the HCN4 gene in a girl who had a single generalized tonic-clonic seizures at 17 years of age. The variant, which was found by direct sequencing, was not present in the ExAC database. However, there were 4 additional family members with various types of seizures who did not carry the variant. Electrophysiologic studies showed that the variant caused a hyperpolarizing shift in the voltage dependence of activation, resulting in reduced function at a physiologic relevant voltage range. The authors suggested that the variant alone is unlikely to cause epilepsy, but that it may contribute along with variants in other genes to the polygenic nature of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29588962" 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 S84L mutation (<a href="#0006">605206.0006</a>) in the HCN4 gene has been reclassified as a variant of unknown significance. In a 64-year-old woman with Brugada syndrome, <a href="#3" class="mim-tip-reference" title="Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J. <strong>Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing.</strong> J. Am. Coll. Cardiol. 60: 1410-1418, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22840528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22840528</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22840528[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.04.037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22840528">Crotti et al. (2012)</a> identified a heterozygous missense mutation in the HCN4 gene (S84L; <a href="#0006">605206.0006</a>). The woman was 1 of 129 unrelated patients with possible or probable Brugada syndrome who were screened for mutation in 12 Brugada syndrome 'susceptibility genes.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22840528" 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="#15" class="mim-tip-reference" title="Stieber, J., Herrmann, S., Feil, S., Loster, J., Feil, R., Biel, M., Hofmann, F., Ludwig, A. <strong>The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in embryonic heart.</strong> Proc. Nat. Acad. Sci. 100: 15235-15240, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14657344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.2434235100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14657344">Stieber et al. (2003)</a> found that Hcn4 +/- mice were viable, bred normally, and were indistinguishable from wildtype littermates. However, Hcn4 -/- embryos died at about embryonic day 9.5. Cardiac-specific deletion of Hcn4 resulted in the same embryonic lethality as global deletion. Hcn4-deleted embryos had slower heart rates than wildtype, and no mature pacemaker-like action potentials were detected, although there were immature pacemaker-like action potentials. The heart rate and action potential rate could not be accelerated by cAMP. <a href="#15" class="mim-tip-reference" title="Stieber, J., Herrmann, S., Feil, S., Loster, J., Feil, R., Biel, M., Hofmann, F., Ludwig, A. <strong>The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in embryonic heart.</strong> Proc. Nat. Acad. Sci. 100: 15235-15240, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14657344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.2434235100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14657344">Stieber et al. (2003)</a> concluded that HCN4 is essential for the proper generation of pacemaker potentials in the emerging sinoatrial node. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14657344" 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=605206[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894488;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/rs104894488?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=rs104894488" 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=rs104894488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#7" class="mim-tip-reference" title="Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D. <strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong> New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407510</a>] [<a href="https://doi.org/10.1056/NEJMoa052475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407510">Milanesi et al. (2006)</a> screened 52 persons with bradycardia (SSS2; <a href="/entry/163800">163800</a>) for mutations in the coding region of the pacemaker gene HCN4. They identified the proband of an Italian family who had asymptomatic sinus bradycardia (heart rate, 43 beats per minute) and carried a missense mutation in exon 7, ser672 to arg (S672R), which arose from a C-to-A transversion at nucleotide 2016. They then examined DNA from a total of 27 members of the same family. PCR-SSCP analysis showed that the S672R mutation cosegregated with the bradycardia phenotype, indicating an autosomal dominant pattern. The heart rate varied from 43 to 60 beats per minute in persons with the mutated gene and from 64 to 81 beats per minute in those with the wildtype gene. <a href="#7" class="mim-tip-reference" title="Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D. <strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong> New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407510</a>] [<a href="https://doi.org/10.1056/NEJMoa052475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407510">Milanesi et al. (2006)</a> calculated a maximum lod score of 5.47 for linkage between HCN4 and bradycardia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 66-year-old woman who had severe syncope with marked sinus bradycardia and intermittent atrial fibrillation (SSS2; <a href="/entry/163800">163800</a>), <a href="#10" class="mim-tip-reference" title="Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D. <strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong> J. Clin. Invest. 111: 1537-1545, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[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/JCI16387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750403">Schulze-Bahr et al. (2003)</a> identified heterozygosity for a 1-bp deletion (1631delC) in exon 5 of the HCN4 gene, causing a frameshift resulting in a truncated protein at codon 573 lacking the C-terminal cyclic nucleotide-binding domain. The mutation was not found in 3 unaffected children or in 362 control chromosomes. Transiently transfected COS-7 cells showed normal intracellular trafficking and membrane integration of mutant subunits; patch-clamp experiments revealed that mutant channels were insensitive to increased cellular cAMP levels and coexpression studies showed a dominant-negative effect of the mutant subunits on wildtype subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750403" 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> rs104894485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894485;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/rs104894485?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=rs104894485" 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=rs104894485" 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=RCV000005483 OR RCV001851666" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005483, RCV001851666" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005483...</a>
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<p>In a 43-year-old woman with sick sinus syndrome (SSS2; <a href="/entry/163800">163800</a>), <a href="#17" class="mim-tip-reference" title="Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A. <strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong> J. Biol. Chem. 279: 27194-27198, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123648</a>] [<a href="https://doi.org/10.1074/jbc.M311953200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15123648">Ueda et al. (2004)</a> identified heterozygosity for a G-A transition in exon 5 of the HCN4 gene, resulting in an asp553-to-asn (D553N) substitution at a conserved residue in the linker region between the core transmembrane domain and the cyclic nucleotide binding domain. The patient's affected sister and son were also heterozygous for the mutation, which was not present in 380 control chromosomes. Studies in transfected COS-7 cells showed that coexpression of the mutant channels reduced the cell surface expression of normal channels in a dominant-negative manner, with decreased I(f) current amplitude by patch clamp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123648" 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 SICK SINUS SYNDROME 2</strong>
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HCN4, GLY480ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908411 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908411;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=rs121908411" 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=rs121908411" 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=RCV000005484" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005484" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005484</a>
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<p>In 8 affected members of a 4-generation family with asymptomatic sinus bradycardia (SSS2; <a href="/entry/163800">163800</a>), <a href="#9" class="mim-tip-reference" title="Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M. <strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong> Circulation 116: 463-470, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646576</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.706887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646576">Nof et al. (2007)</a> identified heterozygosity for a 1439G-C transversion in exon 4 of the HCN4 gene, resulting in a gly480-to-arg (G480R) substitution at a conserved residue within the transmembrane pore-forming region. The mutation was not found in 8 unaffected family members or in 100 unrelated control chromosomes. Functional analysis revealed that mutant channels were activated at more negative voltages than wildtype; expression studies demonstrated a reduction in synthesis and a trafficking defect in mutant channels compared to wildtype channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646576" 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 BRUGADA SYNDROME 8</strong>
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HCN4, 4-BP INS, GTGA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205418 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205418;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=rs786205418" 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=rs786205418" 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=RCV000005485 OR RCV000171564 OR RCV002345233" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005485, RCV000171564, RCV002345233" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005485...</a>
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<p>In a 41-year-old man with Brugada syndrome (BRGDA8; <a href="/entry/613123">613123</a>), <a href="#16" class="mim-tip-reference" title="Ueda, K., Hirano, Y., Higashiuesato, Y., Aizawa, Y., Hayashi, T., Inagaki, N., Tana, T., Ohya, Y., Takishita, S., Muratani, H., Hiraoka, M., Kimura, A. <strong>Role of HCN4 channel in preventing ventricular arrhythmia.</strong> J. Hum. Genet. 54: 115-121, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165230</a>] [<a href="https://doi.org/10.1038/jhg.2008.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19165230">Ueda et al. (2009)</a> identified heterozygosity for a 4-bp insertion (GTGA) at the splice junction donor site of exon 2 and intron 2 of the HCN4 gene, predicted to cause a frameshift and the addition of 44 nonrelevant C-terminal residues and premature termination. Transfection studies in COS-7 cells revealed that the additional 4 bases are incorporated into mRNA, and the SSCP profile showed expression of almost equal amounts of normal and abnormal splicing products. The mutation was not found in 190 healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0006 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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HCN4, SER841LEU
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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> rs200546024 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200546024;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/rs200546024?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=rs200546024" 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=rs200546024" 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=RCV000170941 OR RCV000223954 OR RCV002453581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170941, RCV000223954, RCV002453581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170941...</a>
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<p>This variant, formerly titled BRUGADA SYNDROME 8, has been reclassified based on a review of the gnomAD database by <a href="#5" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 10/21/2022."None>Hamosh (2022)</a>.</p><p>In a 64-year-old woman with Brugada syndrome (BRGDA8; <a href="/entry/613123">613123</a>), <a href="#3" class="mim-tip-reference" title="Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J. <strong>Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing.</strong> J. Am. Coll. Cardiol. 60: 1410-1418, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22840528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22840528</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22840528[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.04.037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22840528">Crotti et al. (2012)</a> identified a heterozygous c.2522C-T transition in exon 8 of the HCN4 gene, resulting in a ser841-to-leu (S841L) substitution. The woman was asymptomatic and had no family history of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22840528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 10/21/2022."None>Hamosh (2022)</a> noted that the S841L variant was present in 18 of 10,168 Ashkenazi Jews in the gnomAD database, with an allelic frequency of 0.001770, calling the pathogenicity of this variant into question.</p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 SICK SINUS SYNDROME 2 WITH CARDIAC NONCOMPACTION AND ASCENDING AORTA DILATION</strong>
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HCN4, 13-BP INS, EX6
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519274 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519274;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=rs1057519274" 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=rs1057519274" 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=RCV000415565" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415565" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415565</a>
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<p>In 8 affected members of a 4-generation German family with marked sinus bradycardia and sinus arrhythmias (SSS2; <a href="/entry/163800">163800</a>), <a href="#11" class="mim-tip-reference" title="Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M. <strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong> Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>] [<a href="https://doi.org/10.1161/CIRCEP.110.949768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20693575">Schweizer et al. (2010)</a> identified heterozygosity for a 13-bp insertion in exon 6 of the HCN4 gene, causing a frameshift predicted to result in a premature termination codon, which the authors designated '695X.' The mutation segregated fully with disease in the family and was not found in 526 controls. Whole-cell patch-clamp recording in transiently transfected HEK293 cells demonstrated that mutant subunits were insensitive to cAMP, and heteromeric channels composed of wildtype and mutant subunits also failed to respond to cAMP, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> reexamined 5 affected individuals from this family and observed biventricular hypertrabeculation and mitral valve prolapse in all 5. <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reviewed the imaging studies from 6 family members and detected dilation of the aortic root in 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25145518+27173043+20693575" 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>.0008 SICK SINUS SYNDROME 2 WITH CARDIAC NONCOMPACTION AND ASCENDING AORTA DILATION</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">rs794727637 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727637;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=rs794727637" 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=rs794727637" 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=RCV000415605 OR RCV001729574 OR RCV001861463" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415605, RCV001729574, RCV001861463" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415605...</a>
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<p>In 7 affected members of a large Dutch family (family A) with bradycardia and left ventricular noncompaction (SSS2; <a href="/entry/163800">163800</a>), <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> identified heterozygosity for a c.1444G-C transversion in exon 4 of the HCN4 gene, resulting in a gly482-to-arg (G482R) substitution at a highly conserved residue within the pore-forming channel domain. The mutation segregated fully with disease in the family and was not found in 500 Dutch controls or in the Exome Sequencing Project database. Functional analysis in CHO cells showed a large negative shift in voltage dependence of activation with mutant channels compared to wildtype, resulting in significantly lower current density, consistent with the observed bradycardia. Mitral valve prolapse (MVP) requiring surgical repair was present in 2 of the affected family members. <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reviewed imaging studies available from 5 of the affected members of this family and found that 3 patients showed dilation of the ascending aorta. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27173043+25145517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a mother and son and daughter from a German family with sinus node disease, left ventricular noncompaction, and MVP, <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> identified heterozygosity for the G482R substitution in the HCN4 gene. Whole-cell patch-clamp analysis in HEK293 cells showed that mutant subunits were nonfunctional, and heteromeric channels composed of mutant and wildtype HCN4 subunits exhibited an approximately 65% reduction in current compared to wildtype channels, indicating a dominant-negative effect as the primary mechanism of I(f) current reduction in heterozygous patients. Because there were no changes in activation or deactivation parameters, <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> concluded that defective ion permeation was the underlying mechanism. <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reviewed imaging studies in the 3 affected individuals and observed that all 3 had dilation of the ascending aorta. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25145518+27173043" 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">rs1057519275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519275;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=rs1057519275" 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=rs1057519275" 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=RCV000415538 OR RCV000693647 OR RCV001529223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415538, RCV000693647, RCV001529223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415538...</a>
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<p>In 4 affected individuals from 2 families (families B and D) with bradycardia and left ventricular noncompaction (SSS2; <a href="/entry/163800">163800</a>), <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> identified heterozygosity for a c.1441T-C transition in exon 4 of the HCN4 gene, resulting in a tyr481-to-his (Y481H) substitution at a highly conserved residue within the pore-forming channel domain. Haplotype analysis was consistent with a common ancestral haplotype in the 2 families. The mutation was not found in 500 Dutch controls or in the Exome Sequencing Project database. <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reviewed imaging studies available from 3 of the affected individuals, and observed that 2 patients also had dilation of the ascending aorta. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27173043+25145517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with sinus bradycardia, noncompaction cardiomyopathy, defects of the mitral valve, and dilation of the ascending aorta, <a href="#18" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> identified the Y481H mutation in the HCN4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27173043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a father and 2 sons (family C) with bradycardia and left ventricular noncompaction (SSS2; <a href="/entry/163800">163800</a>), <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> identified heterozygosity for a c.1241C-G transversion in exon 3 of the HCN4 gene, resulting in an ala414-to-gly (A414G) substitution at a highly conserved residue between the S4 and S5 transmembrane domains. The mutation was not found in 500 Dutch controls or in the Exome Sequencing Project database. Functional analysis in CHO cells showed a large negative shift in voltage dependence of activation with mutant channels compared to wildtype, resulting in significantly lower current density, consistent with the observed bradycardia. Both sons also exhibited left ventricular hypertrophy, with interventricular septa measuring 13 mm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 18 (1 family)</strong>
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HCN4, ARG550CYS (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150691273;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs150691273</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs150691273 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150691273;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/rs150691273?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=rs150691273" 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=rs150691273" 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=RCV001637975 OR RCV003505178 OR RCV004039545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001637975, RCV003505178, RCV004039545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001637975...</a>
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<p>In 2 brothers with idiopathic generalized epilepsy-18 (EIG18; <a href="/entry/619521">619521</a>), <a href="#2" class="mim-tip-reference" title="Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D. <strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong> Front. Molec. Neurosci. 11: 269, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30127718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30127718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30127718[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/10.3389/fnmol.2018.00269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30127718">Campostrini et al. (2018)</a> identified a heterozygous c.1648C-T transition (c.1648C-T, NM_005477) in the HCN4 gene, resulting in an arg550-to-cys (R550C) substitution at a conserved residue in the intracellular B-prime helix domain of the C linker. The mutation, which was found by sequencing of a custom gene panel, was inherited from their father who had an unknown early medical history. The authors stated that the variant was present at a low frequency (8.122 x 10(-06)) in the general population in the gnomAD database. Electrophysiologic studies in CHO cells showed that the mutation caused a negative shift in the activation curve compared to wildtype, consistent with a loss of channel function. Neuronal hyperexcitability and increased firing was observed in neuronal cells transfected with the mutation, which exerted a dominant effect when coexpressed with wildtype. Similar electrophysiologic findings were found in rat ventricular cardiomyocytes transfected with the mutation. Although neither the affected brothers nor their father had clinical cardiac abnormalities, all had low resting heart rates. <a href="#2" class="mim-tip-reference" title="Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D. <strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong> Front. Molec. Neurosci. 11: 269, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30127718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30127718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30127718[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/10.3389/fnmol.2018.00269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30127718">Campostrini et al. (2018)</a> concluded that reduced HCN4 current contribution may affect input membrane resistance and resting membrane potential, causing cell hyperexcitability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30127718" 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>Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy.</strong>
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Epilepsia Open 2: 334-342, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29588962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29588962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29588962[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=29588962" 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/epi4.12068" target="_blank">Full Text</a>]
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Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D.
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<strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong>
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Front. Molec. Neurosci. 11: 269, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30127718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30127718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30127718[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=30127718" 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/10.3389/fnmol.2018.00269" target="_blank">Full Text</a>]
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Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J.
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[<a href="https://doi.org/10.1016/j.jacc.2012.04.037" target="_blank">Full Text</a>]
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Gauss, R., Seifert, R., Kaupp, U. B.
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<strong>Molecular identification of a hyperpolarization-activated channel in sea urchin sperm.</strong>
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Nature 393: 583-587, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634235</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/31248" target="_blank">Full Text</a>]
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 10/21/2022.
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Ludwig, A., Zong, X., Stieber, J., Hullin, R., Hofmann, F., Biel, M.
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<strong>Two pacemaker channels from human heart with profoundly different activation kinetics.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10228147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10228147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10228147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/emboj/18.9.2323" target="_blank">Full Text</a>]
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Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D.
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<strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407510</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407510" 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/NEJMoa052475" target="_blank">Full Text</a>]
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<a id="Milano2014" class="mim-anchor"></a>
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Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R.
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<strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong>
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J. Am. Coll. Cardiol. 64: 745-756, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank">Full Text</a>]
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Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M.
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<strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong>
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Circulation 116: 463-470, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646576</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646576" 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.107.706887" target="_blank">Full Text</a>]
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Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D.
|
|
<strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong>
|
|
J. Clin. Invest. 111: 1537-1545, 2003.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[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=12750403" 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/JCI16387" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Schweizer2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M.
|
|
<strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong>
|
|
Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20693575" 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/CIRCEP.110.949768" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Schweizer2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D.
|
|
<strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong>
|
|
J. Am. Coll. Cardiol. 64: 757-767, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Seifert1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B.
|
|
<strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong>
|
|
Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10430953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10430953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10430953[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=10430953" 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.96.16.9391" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Stevens2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U. B., Lindemann, B.
|
|
<strong>Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.</strong>
|
|
Nature 413: 631-635, 2001.
|
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675786</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11675786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/35098087" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Stieber2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stieber, J., Herrmann, S., Feil, S., Loster, J., Feil, R., Biel, M., Hofmann, F., Ludwig, A.
|
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<strong>The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in embryonic heart.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 15235-15240, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14657344[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=14657344" 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.2434235100" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Ueda2009" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Ueda, K., Hirano, Y., Higashiuesato, Y., Aizawa, Y., Hayashi, T., Inagaki, N., Tana, T., Ohya, Y., Takishita, S., Muratani, H., Hiraoka, M., Kimura, A.
|
|
<strong>Role of HCN4 channel in preventing ventricular arrhythmia.</strong>
|
|
J. Hum. Genet. 54: 115-121, 2009.
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|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165230</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/jhg.2008.16" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Ueda2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A.
|
|
<strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong>
|
|
J. Biol. Chem. 279: 27194-27198, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123648" 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.M311953200" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Vermeer2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I.
|
|
<strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong>
|
|
J. Am. Coll. Cardiol. 67: 2313-2315, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27173043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/21/2022
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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">
|
|
Cassandra L. Kniffin - updated : 09/07/2021<br>Marla J. F. O'Neill - updated : 01/12/2017<br>Carol A. Bocchini - updated : 06/02/2016<br>Marla J. F. O'Neill - updated : 11/18/2009<br>Marla J. F. O'Neill - updated : 3/5/2008<br>Victor A. McKusick - updated : 2/1/2006<br>Patricia A. Hartz - updated : 12/15/2005
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Ada Hamosh : 8/9/2000
|
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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carol : 10/22/2022
|
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</span>
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</div>
|
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
carol : 10/21/2022<br>alopez : 09/09/2021<br>ckniffin : 09/07/2021<br>carol : 01/17/2018<br>carol : 03/06/2017<br>carol : 01/12/2017<br>carol : 06/02/2016<br>carol : 5/23/2016<br>carol : 9/16/2013<br>terry : 12/20/2012<br>carol : 12/15/2011<br>wwang : 11/18/2009<br>wwang : 7/28/2008<br>wwang : 3/5/2008<br>alopez : 2/15/2006<br>terry : 2/1/2006<br>wwang : 12/20/2005<br>wwang : 12/15/2005<br>alopez : 10/16/2001<br>alopez : 8/9/2000
|
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
|
<strong>*</strong> 605206
|
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</span>
|
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</h3>
|
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</div>
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|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL 4; HCN4
|
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</span>
|
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: HCN4</em></strong>
|
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</span>
|
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</p>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 15q24.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 15:73,319,859-73,368,958 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<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>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
15q24.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Epilepsy, idiopathic generalized, susceptibility to, 18}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619521
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Brugada syndrome 8
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613123
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<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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<tr>
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<td>
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<span class="mim-font">
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Sick sinus 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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163800
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The HCN4 gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated ion channel family, which are expressed at the cell membrane and contribute to the resting membrane potential. HCN4 is expressed in the heart and in several brain regions, including the thalamus (summary by Campostrini et al., 2018). </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>Cardiac pacemaking is produced by the slow diastolic depolarization phase of the action potential. The hyperpolarization-activated cation current forms an important part of the pacemaker depolarization and consists of 2 kinetic components, fast and slow. To elucidate the molecular identity of cardiac pacemaking channels, Ludwig et al. (1999) screened a human heart cDNA library with a probe corresponding to a highly conserved portion of the mouse HCN1 (602780) channel and identified 2 cDNAs, HCN2 (602781) and HCN4. The HCN4 cDNA predicts a protein of 1,203 amino acids. HCN4 contains 6 putative transmembrane segments, a pore region, and a cyclic nucleotide-binding domain (CNBD). Northern blot and PCR analyses showed that HCN4 is expressed at heart ventricle and atrium. </p><p>Seifert et al. (1999) independently cloned HCN4. Northern blot analysis showed the HCN4 transcripts were expressed in heart, brain, and testis. Within the brain, the thalamus is the predominant area of HCN4 expression. </p><p>By in situ hybridization and immunohistochemical analysis of mouse embryos at embryonic day 10.5, Stieber et al. (2003) detected high levels of Hcn4 mRNA and protein in developing embryonic cardiac regions, including the walls of the common cardinal veins entering the sinus venosa. Much lower expression was detected in the developing central nervous system. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Schulze-Bahr et al. (2003) determined that the HCN4 gene contains 8 coding exons. </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>Seifert et al. (1999) mapped the HCN4 gene to chromosome band 15q24-q25 by FISH. By genomic sequence analysis, Schulze-Bahr et al. (2003) mapped the HCN4 gene to chromosome 15q23-q24.1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ludwig et al. (1999) expressed HCN4 in HEK293 cells and observed that HCN4 gives rise to hyperpolarization-activated cation currents with the hallmark features of the native cation current. HCN4 currents differ profoundly from HCN2 currents in their activation kinetics, being slow and fast, respectively. </p><p>Seifert et al. (1999) demonstrated that heterologous expression of HCN4 produced channels of unusually slow kinetics of activation and inactivation. The mean potential of half-maximal activation was -75.2 mV. The characteristic expression pattern and the sluggish gating suggested to Seifert et al. (1999) that HCN4 controls the rhythmic activity in both thalamocortical neurons and pacemaker cells of the heart. The strong hybridization with testis mRNA further suggested to Seifert et al. (1999) that HCN4 is also expressed in mature spermatozoa or their precursor cells. In this respect, HCN4 may represent the mammalian equivalent of the HCN channel in the flagellum of sea urchin spermatozoa (Gauss et al., 1998). Seifert et al. (1999) proposed that both the sea urchin channel and the human HCN4 may be involved in the generation of rhythmic activity that controls the waveform of flagellar beating. </p><p>Sour taste is initiated by protons acting at receptor proteins or channels. Stevens et al. (2001) examined the effects of sour stimuli on taste cells in slices of vallate papilla from rat. From a subset of cells, Stevens et al. (2001) identified a hyperpolarization-activated current that was enhanced by sour stimulation at the taste pore. This current resembled I(h) found in neurons and cardiomyocytes, a current carried by members of the family of hyperpolarization-activated and cyclic-nucleotide-gated (HCN) channels. Stevens et al. (2001) showed by in situ hybridization and immunohistochemistry that HCN1 and HCN4 are expressed in a subset of taste cells. By contrast, gustducin (139395), the G protein involved in bitter and sweet taste, was not expressed in these cells. Stevens et al. (2001) concluded that HCN channels are gated by extracellular protons and may act as receptors for sour taste. </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>Sick Sinus Syndrome 2</em></strong></p><p>
|
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In a 66-year-old woman with symptomatic sinus bradycardia (SSS2; 163800), Schulze-Bahr et al. (2003) identified heterozygosity for a 1-bp deletion (605206.0002) in the HCN4 gene that was not found in 362 control chromosomes. Patch-clamp experiments in COS-7 cells demonstrated that the mutant channels mediated I(f) currents that were insensitive to increased cellular cAMP levels; coexpression studies showed a dominant-negative effect of the mutant subunits on wildtype subunits. </p><p>Ueda et al. (2004) analyzed the HCN4 gene in 6 patients with sinus node dysfunction, 3 patients with progressive cardiac conduction disturbances, and 14 patients with idiopathic ventricular fibrillation, all of whom were negative for mutations in 6 known ion channel genes, and identified heterozygosity for a mutation in 1 proband with sinus node dysfunction (D553N; 605206.0003). The mutation was also found in the proband's affected sister and son, and was not present in 380 control chromosomes. In vitro analysis showed reduced membrane expression associated with decreased I(f) currents because of a trafficking defect of the HCN4 channel in a dominant-negative fashion. </p><p>Milanesi et al. (2006) found that sinus bradycardia was associated with a mutation (605206.0001) in the gene encoding the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cAMP-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis showed that mutant channels respond normally to cAMP but are activated at more negative voltages than are wildtype channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia. </p><p>In 8 affected members of a 4-generation family with asymptomatic sinus bradycardia, Nof et al. (2007) identified a heterozygous mutation in the HCN4 gene (G480R; 605206.0004). </p><p>In a 4-generation German family with sinus bradycardia, biventricular hypertrabeculation, and mitral valve prolapse (MVP), Schweizer et al. (2010) identified heterozygosity for a 13-bp insertion in the HCN4 gene (605206.0007) that segregated fully with disease. </p><p>In affected members of a large Dutch family with bradycardia, left ventricular noncompaction (LVNC), and MVP, Milano et al. (2014) identified heterozygosity for a missense mutation in the HCN4 gene (G482R; 605206.0008). Analysis of HCN4 in 3 families with a similar phenotype revealed heterozygosity for a Y481H mutation (605206.0009) in 2 of them, and an A414G mutation (605206.0010) in the third. The mutations segregated with disease in each family and were not found in controls or in public variant databases. </p><p>In a German mother and 2 children with sinus node dysfunction, LVNC, and MVP, Schweizer et al. (2014) identified heterozygosity for the G482R mutation in the HCN4 gene. In addition, the mother was homozygous and the 2 children heterozygous for a variant of unknown significance in the CSRP3 gene (W4R; see 600824.0001); the authors stated that this variant was unlikely to be a primary cause of the cardiac noncompaction phenotype, but suggested that it might make a modifying contribution. </p><p>In a family with sinus bradycardia, LVNC, MVP, and dilation of the ascending aorta, Vermeer et al. (2016) identified the Y481H mutation in the HCN4 gene. Vermeer et al. (2016) reviewed multimodal imaging studies available from previously described patients with HCN4 mutations (Schweizer et al., 2014; Milano et al., 2014) and detected dilation of the ascending aorta in 13 of 18 patients with adequate studies, for an overall detection rate of 77% in HCN4 mutation carriers. </p><p><strong><em>Brugada Syndrome 8</em></strong></p><p>
|
|
In a 41-year-old man with Brugada syndrome-8 (BRGDA8; 613123) who was negative for mutation in the SCN5A gene (600163), Ueda et al. (2009) identified heterozygosity for a splice site mutation in the HCN4 gene (605206.0005). </p><p><strong><em>Susceptibility to Idiopathic Generalized Epilepsy 18</em></strong></p><p>
|
|
In 2 brothers with idiopathic generalized epilepsy-18 (EIG18; 619521), Campostrini et al. (2018) identified a heterozygous missense mutation in the HCN4 gene (R550C; 605206.0011). Electrophysiologic studies in CHO cells showed that the mutation caused a negative shift in the activation curve compared to wildtype, consistent with a loss of channel function. Neuronal hyperexcitability and increased firing was observed in neuronal cells transfected with the mutation, which exerted a dominant effect when coexpressed with wildtype. Campostrini et al. (2018) concluded that reduced HCN4 current contribution may affect input membrane resistance and resting membrane potential, causing cell hyperexcitability. </p><p>Becker et al. (2017) identified a heterozygous missense variant (E153G) in the HCN4 gene in a girl who had a single generalized tonic-clonic seizures at 17 years of age. The variant, which was found by direct sequencing, was not present in the ExAC database. However, there were 4 additional family members with various types of seizures who did not carry the variant. Electrophysiologic studies showed that the variant caused a hyperpolarizing shift in the voltage dependence of activation, resulting in reduced function at a physiologic relevant voltage range. The authors suggested that the variant alone is unlikely to cause epilepsy, but that it may contribute along with variants in other genes to the polygenic nature of the disorder. </p><p><strong><em>Reclassified Variants</em></strong></p><p>
|
|
The S84L mutation (605206.0006) in the HCN4 gene has been reclassified as a variant of unknown significance. In a 64-year-old woman with Brugada syndrome, Crotti et al. (2012) identified a heterozygous missense mutation in the HCN4 gene (S84L; 605206.0006). The woman was 1 of 129 unrelated patients with possible or probable Brugada syndrome who were screened for mutation in 12 Brugada syndrome 'susceptibility genes.' </p>
|
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</span>
|
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<div>
|
|
<br />
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|
</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
|
|
<span class="mim-text-font">
|
|
<p>Stieber et al. (2003) found that Hcn4 +/- mice were viable, bred normally, and were indistinguishable from wildtype littermates. However, Hcn4 -/- embryos died at about embryonic day 9.5. Cardiac-specific deletion of Hcn4 resulted in the same embryonic lethality as global deletion. Hcn4-deleted embryos had slower heart rates than wildtype, and no mature pacemaker-like action potentials were detected, although there were immature pacemaker-like action potentials. The heart rate and action potential rate could not be accelerated by cAMP. Stieber et al. (2003) concluded that HCN4 is essential for the proper generation of pacemaker potentials in the emerging sinoatrial node. </p>
|
|
</span>
|
|
<div>
|
|
<br />
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</div>
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|
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|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>11 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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|
<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 SICK SINUS SYNDROME 2</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
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|
HCN4, SER672ARG
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<br />
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|
|
SNP: rs104894488,
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|
|
|
gnomAD: rs104894488,
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|
|
ClinVar: RCV000005481
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Milanesi et al. (2006) screened 52 persons with bradycardia (SSS2; 163800) for mutations in the coding region of the pacemaker gene HCN4. They identified the proband of an Italian family who had asymptomatic sinus bradycardia (heart rate, 43 beats per minute) and carried a missense mutation in exon 7, ser672 to arg (S672R), which arose from a C-to-A transversion at nucleotide 2016. They then examined DNA from a total of 27 members of the same family. PCR-SSCP analysis showed that the S672R mutation cosegregated with the bradycardia phenotype, indicating an autosomal dominant pattern. The heart rate varied from 43 to 60 beats per minute in persons with the mutated gene and from 64 to 81 beats per minute in those with the wildtype gene. Milanesi et al. (2006) calculated a maximum lod score of 5.47 for linkage between HCN4 and bradycardia. </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>.0002 SICK SINUS SYNDROME 2</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
|
HCN4, 1-BP DEL, 1631C
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<br />
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|
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SNP: rs1057519015,
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|
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ClinVar: RCV000005482
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</span>
|
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</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 66-year-old woman who had severe syncope with marked sinus bradycardia and intermittent atrial fibrillation (SSS2; 163800), Schulze-Bahr et al. (2003) identified heterozygosity for a 1-bp deletion (1631delC) in exon 5 of the HCN4 gene, causing a frameshift resulting in a truncated protein at codon 573 lacking the C-terminal cyclic nucleotide-binding domain. The mutation was not found in 3 unaffected children or in 362 control chromosomes. Transiently transfected COS-7 cells showed normal intracellular trafficking and membrane integration of mutant subunits; patch-clamp experiments revealed that mutant channels were insensitive to increased cellular cAMP levels and coexpression studies showed a dominant-negative effect of the mutant subunits on wildtype subunits. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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|
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 SICK SINUS SYNDROME 2</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
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HCN4, ASP553ASN
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<br />
|
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|
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SNP: rs104894485,
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|
|
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gnomAD: rs104894485,
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|
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ClinVar: RCV000005483, RCV001851666
|
|
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</span>
|
|
</div>
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 43-year-old woman with sick sinus syndrome (SSS2; 163800), Ueda et al. (2004) identified heterozygosity for a G-A transition in exon 5 of the HCN4 gene, resulting in an asp553-to-asn (D553N) substitution at a conserved residue in the linker region between the core transmembrane domain and the cyclic nucleotide binding domain. The patient's affected sister and son were also heterozygous for the mutation, which was not present in 380 control chromosomes. Studies in transfected COS-7 cells showed that coexpression of the mutant channels reduced the cell surface expression of normal channels in a dominant-negative manner, with decreased I(f) current amplitude by patch clamp. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 SICK SINUS 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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HCN4, GLY480ARG
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<br />
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|
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SNP: rs121908411,
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ClinVar: RCV000005484
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 affected members of a 4-generation family with asymptomatic sinus bradycardia (SSS2; 163800), Nof et al. (2007) identified heterozygosity for a 1439G-C transversion in exon 4 of the HCN4 gene, resulting in a gly480-to-arg (G480R) substitution at a conserved residue within the transmembrane pore-forming region. The mutation was not found in 8 unaffected family members or in 100 unrelated control chromosomes. Functional analysis revealed that mutant channels were activated at more negative voltages than wildtype; expression studies demonstrated a reduction in synthesis and a trafficking defect in mutant channels compared to wildtype channels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0005 BRUGADA SYNDROME 8</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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HCN4, 4-BP INS, GTGA
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<br />
|
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|
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SNP: rs786205418,
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ClinVar: RCV000005485, RCV000171564, RCV002345233
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 41-year-old man with Brugada syndrome (BRGDA8; 613123), Ueda et al. (2009) identified heterozygosity for a 4-bp insertion (GTGA) at the splice junction donor site of exon 2 and intron 2 of the HCN4 gene, predicted to cause a frameshift and the addition of 44 nonrelevant C-terminal residues and premature termination. Transfection studies in COS-7 cells revealed that the additional 4 bases are incorporated into mRNA, and the SSCP profile showed expression of almost equal amounts of normal and abnormal splicing products. The mutation was not found in 190 healthy controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 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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HCN4, SER841LEU
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<br />
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SNP: rs200546024,
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gnomAD: rs200546024,
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ClinVar: RCV000170941, RCV000223954, RCV002453581
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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 BRUGADA SYNDROME 8, has been reclassified based on a review of the gnomAD database by Hamosh (2022).</p><p>In a 64-year-old woman with Brugada syndrome (BRGDA8; 613123), Crotti et al. (2012) identified a heterozygous c.2522C-T transition in exon 8 of the HCN4 gene, resulting in a ser841-to-leu (S841L) substitution. The woman was asymptomatic and had no family history of the disorder. </p><p>Hamosh (2022) noted that the S841L variant was present in 18 of 10,168 Ashkenazi Jews in the gnomAD database, with an allelic frequency of 0.001770, calling the pathogenicity of this variant 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">
|
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<strong>.0007 SICK SINUS SYNDROME 2 WITH CARDIAC NONCOMPACTION AND ASCENDING AORTA DILATION</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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HCN4, 13-BP INS, EX6
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<br />
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SNP: rs1057519274,
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ClinVar: RCV000415565
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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 8 affected members of a 4-generation German family with marked sinus bradycardia and sinus arrhythmias (SSS2; 163800), Schweizer et al. (2010) identified heterozygosity for a 13-bp insertion in exon 6 of the HCN4 gene, causing a frameshift predicted to result in a premature termination codon, which the authors designated '695X.' The mutation segregated fully with disease in the family and was not found in 526 controls. Whole-cell patch-clamp recording in transiently transfected HEK293 cells demonstrated that mutant subunits were insensitive to cAMP, and heteromeric channels composed of wildtype and mutant subunits also failed to respond to cAMP, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Schweizer et al. (2014) reexamined 5 affected individuals from this family and observed biventricular hypertrabeculation and mitral valve prolapse in all 5. Vermeer et al. (2016) reviewed the imaging studies from 6 family members and detected dilation of the aortic root in 4. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 SICK SINUS SYNDROME 2 WITH CARDIAC NONCOMPACTION AND ASCENDING AORTA DILATION</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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HCN4, GLY482ARG
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<br />
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SNP: rs794727637,
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ClinVar: RCV000415605, RCV001729574, RCV001861463
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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 7 affected members of a large Dutch family (family A) with bradycardia and left ventricular noncompaction (SSS2; 163800), Milano et al. (2014) identified heterozygosity for a c.1444G-C transversion in exon 4 of the HCN4 gene, resulting in a gly482-to-arg (G482R) substitution at a highly conserved residue within the pore-forming channel domain. The mutation segregated fully with disease in the family and was not found in 500 Dutch controls or in the Exome Sequencing Project database. Functional analysis in CHO cells showed a large negative shift in voltage dependence of activation with mutant channels compared to wildtype, resulting in significantly lower current density, consistent with the observed bradycardia. Mitral valve prolapse (MVP) requiring surgical repair was present in 2 of the affected family members. Vermeer et al. (2016) reviewed imaging studies available from 5 of the affected members of this family and found that 3 patients showed dilation of the ascending aorta. </p><p>In a mother and son and daughter from a German family with sinus node disease, left ventricular noncompaction, and MVP, Schweizer et al. (2014) identified heterozygosity for the G482R substitution in the HCN4 gene. Whole-cell patch-clamp analysis in HEK293 cells showed that mutant subunits were nonfunctional, and heteromeric channels composed of mutant and wildtype HCN4 subunits exhibited an approximately 65% reduction in current compared to wildtype channels, indicating a dominant-negative effect as the primary mechanism of I(f) current reduction in heterozygous patients. Because there were no changes in activation or deactivation parameters, Schweizer et al. (2014) concluded that defective ion permeation was the underlying mechanism. Vermeer et al. (2016) reviewed imaging studies in the 3 affected individuals and observed that all 3 had dilation of the ascending aorta. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 SICK SINUS SYNDROME 2 WITH CARDIAC NONCOMPACTION AND ASCENDING AORTA DILATION</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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HCN4, TYR481HIS
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<br />
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SNP: rs1057519275,
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ClinVar: RCV000415538, RCV000693647, RCV001529223
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected individuals from 2 families (families B and D) with bradycardia and left ventricular noncompaction (SSS2; 163800), Milano et al. (2014) identified heterozygosity for a c.1441T-C transition in exon 4 of the HCN4 gene, resulting in a tyr481-to-his (Y481H) substitution at a highly conserved residue within the pore-forming channel domain. Haplotype analysis was consistent with a common ancestral haplotype in the 2 families. The mutation was not found in 500 Dutch controls or in the Exome Sequencing Project database. Vermeer et al. (2016) reviewed imaging studies available from 3 of the affected individuals, and observed that 2 patients also had dilation of the ascending aorta. </p><p>In affected members of a family with sinus bradycardia, noncompaction cardiomyopathy, defects of the mitral valve, and dilation of the ascending aorta, Vermeer et al. (2016) identified the Y481H mutation in the HCN4 gene. </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>.0010 SICK SINUS SYNDROME 2 WITH CARDIAC NONCOMPACTION</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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HCN4, ALA414GLY
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<br />
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SNP: rs1057519276,
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ClinVar: RCV000415571
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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 father and 2 sons (family C) with bradycardia and left ventricular noncompaction (SSS2; 163800), Milano et al. (2014) identified heterozygosity for a c.1241C-G transversion in exon 3 of the HCN4 gene, resulting in an ala414-to-gly (A414G) substitution at a highly conserved residue between the S4 and S5 transmembrane domains. The mutation was not found in 500 Dutch controls or in the Exome Sequencing Project database. Functional analysis in CHO cells showed a large negative shift in voltage dependence of activation with mutant channels compared to wildtype, resulting in significantly lower current density, consistent with the observed bradycardia. Both sons also exhibited left ventricular hypertrophy, with interventricular septa measuring 13 mm. </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>.0011 EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 18 (1 family)</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HCN4, ARG550CYS ({dbSNP rs150691273})
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<br />
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SNP: rs150691273,
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gnomAD: rs150691273,
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|
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ClinVar: RCV001637975, RCV003505178, RCV004039545
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 brothers with idiopathic generalized epilepsy-18 (EIG18; 619521), Campostrini et al. (2018) identified a heterozygous c.1648C-T transition (c.1648C-T, NM_005477) in the HCN4 gene, resulting in an arg550-to-cys (R550C) substitution at a conserved residue in the intracellular B-prime helix domain of the C linker. The mutation, which was found by sequencing of a custom gene panel, was inherited from their father who had an unknown early medical history. The authors stated that the variant was present at a low frequency (8.122 x 10(-06)) in the general population in the gnomAD database. Electrophysiologic studies in CHO cells showed that the mutation caused a negative shift in the activation curve compared to wildtype, consistent with a loss of channel function. Neuronal hyperexcitability and increased firing was observed in neuronal cells transfected with the mutation, which exerted a dominant effect when coexpressed with wildtype. Similar electrophysiologic findings were found in rat ventricular cardiomyocytes transfected with the mutation. Although neither the affected brothers nor their father had clinical cardiac abnormalities, all had low resting heart rates. Campostrini et al. (2018) concluded that reduced HCN4 current contribution may affect input membrane resistance and resting membrane potential, causing cell hyperexcitability. </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>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Becker, F., Reid, C. A., Hallmann, K., Tae, H.-S., Phillips, A. M., Teodorescu, G., Weber, Y. G., Kleefuss-Lie, A., Elger, C., Perez-Reyes, E., Petrou, S., Kunz, WS., Lerche, H., Maljevic, S.
|
|
<strong>Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy.</strong>
|
|
Epilepsia Open 2: 334-342, 2017.
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[PubMed: 29588962]
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[Full Text: https://doi.org/10.1002/epi4.12068]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D.
|
|
<strong>A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability.</strong>
|
|
Front. Molec. Neurosci. 11: 269, 2018.
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[PubMed: 30127718]
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[Full Text: https://doi.org/10.3389/fnmol.2018.00269]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J.
|
|
<strong>Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing.</strong>
|
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J. Am. Coll. Cardiol. 60: 1410-1418, 2012.
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[PubMed: 22840528]
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[Full Text: https://doi.org/10.1016/j.jacc.2012.04.037]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gauss, R., Seifert, R., Kaupp, U. B.
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|
<strong>Molecular identification of a hyperpolarization-activated channel in sea urchin sperm.</strong>
|
|
Nature 393: 583-587, 1998.
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|
[PubMed: 9634235]
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[Full Text: https://doi.org/10.1038/31248]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 10/21/2022.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Ludwig, A., Zong, X., Stieber, J., Hullin, R., Hofmann, F., Biel, M.
|
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<strong>Two pacemaker channels from human heart with profoundly different activation kinetics.</strong>
|
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EMBO J. 18: 2323-2329, 1999.
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[PubMed: 10228147]
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[Full Text: https://doi.org/10.1093/emboj/18.9.2323]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D.
|
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<strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong>
|
|
New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.
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[PubMed: 16407510]
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[Full Text: https://doi.org/10.1056/NEJMoa052475]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R.
|
|
<strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong>
|
|
J. Am. Coll. Cardiol. 64: 745-756, 2014.
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[PubMed: 25145517]
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[Full Text: https://doi.org/10.1016/j.jacc.2014.05.045]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M.
|
|
<strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong>
|
|
Circulation 116: 463-470, 2007.
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|
[PubMed: 17646576]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.706887]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D.
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<strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong>
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J. Clin. Invest. 111: 1537-1545, 2003.
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[PubMed: 12750403]
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[Full Text: https://doi.org/10.1172/JCI16387]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M.
|
|
<strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong>
|
|
Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.
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|
|
[PubMed: 20693575]
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[Full Text: https://doi.org/10.1161/CIRCEP.110.949768]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D.
|
|
<strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong>
|
|
J. Am. Coll. Cardiol. 64: 757-767, 2014.
|
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|
|
|
|
[PubMed: 25145518]
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[Full Text: https://doi.org/10.1016/j.jacc.2014.06.1155]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U. B.
|
|
<strong>Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.</strong>
|
|
Proc. Nat. Acad. Sci. 96: 9391-9396, 1999.
|
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|
|
[PubMed: 10430953]
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[Full Text: https://doi.org/10.1073/pnas.96.16.9391]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U. B., Lindemann, B.
|
|
<strong>Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.</strong>
|
|
Nature 413: 631-635, 2001.
|
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|
[PubMed: 11675786]
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[Full Text: https://doi.org/10.1038/35098087]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Stieber, J., Herrmann, S., Feil, S., Loster, J., Feil, R., Biel, M., Hofmann, F., Ludwig, A.
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<strong>The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in embryonic heart.</strong>
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Proc. Nat. Acad. Sci. 100: 15235-15240, 2003.
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[PubMed: 14657344]
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[Full Text: https://doi.org/10.1073/pnas.2434235100]
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Ueda, K., Hirano, Y., Higashiuesato, Y., Aizawa, Y., Hayashi, T., Inagaki, N., Tana, T., Ohya, Y., Takishita, S., Muratani, H., Hiraoka, M., Kimura, A.
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<strong>Role of HCN4 channel in preventing ventricular arrhythmia.</strong>
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J. Hum. Genet. 54: 115-121, 2009.
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[PubMed: 19165230]
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[Full Text: https://doi.org/10.1038/jhg.2008.16]
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Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A.
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<strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong>
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J. Biol. Chem. 279: 27194-27198, 2004.
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[PubMed: 15123648]
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[Full Text: https://doi.org/10.1074/jbc.M311953200]
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Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I.
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<strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong>
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J. Am. Coll. Cardiol. 67: 2313-2315, 2016.
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[PubMed: 27173043]
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[Full Text: https://doi.org/10.1016/j.jacc.2016.01.086]
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Ada Hamosh - updated : 10/21/2022<br>Cassandra L. Kniffin - updated : 09/07/2021<br>Marla J. F. O'Neill - updated : 01/12/2017<br>Carol A. Bocchini - updated : 06/02/2016<br>Marla J. F. O'Neill - updated : 11/18/2009<br>Marla J. F. O'Neill - updated : 3/5/2008<br>Victor A. McKusick - updated : 2/1/2006<br>Patricia A. Hartz - updated : 12/15/2005
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