3971 lines
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3971 lines
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Entry
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- *605411 - POTASSIUM VOLTAGE-GATED CHANNEL, SHAL-RELATED SUBFAMILY, MEMBER 3; KCND3
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- OMIM
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<p>
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<span class="h4">*605411</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605411">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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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<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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</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=ENSG00000171385;t=ENST00000302127" 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=3752" 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=605411" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000171385;t=ENST00000302127" 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_001378969,NM_001378970,NM_004980,NM_172198,XM_006710629,XM_006710632,XM_011541425,XM_011541426,XM_011541427,XM_011541428,XM_017001244,XM_017001245" 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_001378969" 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=605411" 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=16104&isoform_id=16104_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/KCND3" 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/2935434,2935436,5059060,6007795,6007797,6644150,6644152,7715882,7715883,27436984,27436986,61971312,92090984,109731051,109731277,119576914,119576915,119576916,219518797,578799084,578799090,767904241,767904243,767904246,767904248,1034558416,1034558422,1821474368,1821474505,2462508902,2462508904,2462508906,2462508908,2462508910,2462508912,2462508914,2462508916" 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/Q9UK17" 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=3752" 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=ENSG00000171385;t=ENST00000302127" 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=KCND3" 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=KCND3" 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+3752" 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/KCND3" 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:3752" 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/3752" 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=chr1&hgg_gene=ENST00000302127.5&hgg_start=111770662&hgg_end=111989668&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:6239" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605411[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=605411[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/KCND3/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/ENSG00000171385" 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=KCND3" 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=KCND3" 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=KCND3" 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=KCND3&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/PA210" 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:6239" 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/FBgn0005564.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:1928743" 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/KCND3#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:1928743" 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/3752/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=3752" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00022240;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-5626" 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:3752" 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=KCND3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 719251009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
605411
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
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<span class="mim-font">
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POTASSIUM VOLTAGE-GATED CHANNEL, SHAL-RELATED SUBFAMILY, MEMBER 3; KCND3
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
Kv4.3<br />
|
|
KCND3S
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
KCND3L, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KCND3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KCND3</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/919?start=-3&limit=10&highlight=919">1p13.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:111770662-111989668&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'})">1:111,770,662-111,989,668</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616399,607346" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/919?start=-3&limit=10&highlight=919">
|
|
1p13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Brugada syndrome 9
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616399"> 616399 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
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</td>
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|
|
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</tr>
|
|
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|
|
|
|
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 19
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607346"> 607346 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
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<p>The KCND3 gene encodes Kv4.3, an alpha subunit of the Shal family of A-type voltage-gated potassium channels, which are important in membrane repolarization in excitable cells (summary by <a href="#12" class="mim-tip-reference" title="Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., and 10 others. <strong>Mutations in KCND3 cause spinocerebellar ataxia type 22.</strong> Ann. Neurol. 72: 859-869, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23280837[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/ana.23701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280837">Lee et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23280837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By screening a cardiac cDNA library and RT-PCR of human ventricular RNA, <a href="#10" class="mim-tip-reference" title="Kong, W., Po, S., Yamagishi, T., Ashen, M. D., Stetten, G., Tomaselli, G. F. <strong>Isolation and characterization of the human gene encoding I(to): further diversity by alternative mRNA splicing.</strong> Am. J. Physiol. 275: H1963-H1970, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843794</a>] [<a href="https://doi.org/10.1152/ajpheart.1998.275.6.H1963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843794">Kong et al. (1998)</a> isolated a cDNA encoding KCND3. The deduced 637-amino acid protein shares 99% sequence homology with the rat homolog. KCND3 contains 6 transmembrane segments and intracellular N- and C-termini. RT-PCR and sequence analysis demonstrated the existence of a splice variant, KCND3L, with an insert encoding an additional 19 amino acids and containing a phosphorylation site. The shorter isoform was designated KCND3S. <a href="#18" class="mim-tip-reference" title="Zhu, X. R., Wulf, A., Schwarz, M., Isbrandt, D., Pongs, O. <strong>Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current.</strong> Receptors Channels 6: 387-400, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10551270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10551270</a>]" pmid="10551270">Zhu et al. (1999)</a> found that the KCND3L, KCND1 (<a href="/entry/300281">300281</a>), and KCND2 (<a href="/entry/605410">605410</a>) proteins share 60% sequence identity and 71% homology, with the least conservation in the C terminus. By Northern blot analysis, <a href="#10" class="mim-tip-reference" title="Kong, W., Po, S., Yamagishi, T., Ashen, M. D., Stetten, G., Tomaselli, G. F. <strong>Isolation and characterization of the human gene encoding I(to): further diversity by alternative mRNA splicing.</strong> Am. J. Physiol. 275: H1963-H1970, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843794</a>] [<a href="https://doi.org/10.1152/ajpheart.1998.275.6.H1963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843794">Kong et al. (1998)</a> detected expression of an 8.5-kb transcript that is most abundant in brain and heart and is not detectable in kidney, liver, lung, pancreas, spleen, or skeletal muscle. By the same method, <a href="#9" class="mim-tip-reference" title="Isbrandt, D., Leicher, T., Waldschutz, R., Zhu, X., Luhmann, U., Michel, U., Sauter, K., Pongs, O. <strong>Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(to) and I(sa).</strong> Genomics 64: 144-154, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10729221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10729221</a>] [<a href="https://doi.org/10.1006/geno.2000.6117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10729221">Isbrandt et al. (2000)</a> found that expression within the brain is greatest in the cerebral cortex. By RT-PCR analysis, they found that the long transcript predominates in thalamus, caudate nucleus, white matter, and epiphysis, whereas the short transcript is more abundant in frontal cortex, occipital lobe, and cerebellar cortex. <a href="#2" class="mim-tip-reference" title="Dilks, D., Ling, H.-P., Cockett, M., Sokol, P., Numann, R. <strong>Cloning and expression of the human Kv4.3 potassium channel.</strong> J. Neurophysiol. 81: 1974-1977, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10200233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10200233</a>] [<a href="https://doi.org/10.1152/jn.1999.81.4.1974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10200233">Dilks et al. (1999)</a>, who cloned KCND3 from human heart and brain, found by RT-PCR that only the long form of KCND3 is expressed in heart. <a href="#9" class="mim-tip-reference" title="Isbrandt, D., Leicher, T., Waldschutz, R., Zhu, X., Luhmann, U., Michel, U., Sauter, K., Pongs, O. <strong>Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(to) and I(sa).</strong> Genomics 64: 144-154, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10729221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10729221</a>] [<a href="https://doi.org/10.1006/geno.2000.6117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10729221">Isbrandt et al. (2000)</a> determined that the long form of the KCND3 gene contains 7 exons and spans at least 25 kb. The shorter isoform is encoded by 6 exons. <a href="#10" class="mim-tip-reference" title="Kong, W., Po, S., Yamagishi, T., Ashen, M. D., Stetten, G., Tomaselli, G. F. <strong>Isolation and characterization of the human gene encoding I(to): further diversity by alternative mRNA splicing.</strong> Am. J. Physiol. 275: H1963-H1970, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843794</a>] [<a href="https://doi.org/10.1152/ajpheart.1998.275.6.H1963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843794">Kong et al. (1998)</a> and <a href="#2" class="mim-tip-reference" title="Dilks, D., Ling, H.-P., Cockett, M., Sokol, P., Numann, R. <strong>Cloning and expression of the human Kv4.3 potassium channel.</strong> J. Neurophysiol. 81: 1974-1977, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10200233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10200233</a>] [<a href="https://doi.org/10.1152/jn.1999.81.4.1974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10200233">Dilks et al. (1999)</a> found no differences in the splice variants in terms of their voltage dependence or inactivation kinetics in the basal state. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9843794+10551270+10200233+10729221" 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 human cerebellar tissue, <a href="#4" class="mim-tip-reference" title="Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S. <strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong> Ann. Neurol. 72: 870-880, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>] [<a href="https://doi.org/10.1002/ana.23700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280838">Duarri et al. (2012)</a> found weak, punctuated immunostaining for the KCND3 gene in Purkinje cell bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23280838" 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>The transient outward potassium current, I(to), is especially important during the early phase of repolarization in many species, including human, as it sets the plateau voltage of both the atrial and the ventricular action potential. KCND2 and/or KCND3 code for the primary alpha subunits responsible for I(to) (<a href="#16" class="mim-tip-reference" title="Tseng, G.-N. <strong>Molecular structure of cardiac I(to) channels: Kv4.2, Kv4.3, and other possibilities?</strong> Cardiovasc. Res. 41: 16-18, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10325948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10325948</a>] [<a href="https://doi.org/10.1016/s0008-6363(98)00282-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10325948">Tseng, 1999</a>). In the human ventricle, KCND3 is the gene that encodes the K+ channel that underlies I(to) (<a href="#3" class="mim-tip-reference" title="Dixon, J. E., Shi, W., Wang, H.-S., McDonald, C., Yu, H., Wymore, R. S., Cohen, I. S., McKinnon, D. <strong>Role of the Kv4.3 K+ channel in ventricular muscle: a molecular correlate for the transient outward current.</strong> Circ. Res. 79: 659-668, 1996. Note: Erratum: Circ. Res. 80: 147 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8831489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8831489</a>] [<a href="https://doi.org/10.1161/01.res.79.4.659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8831489">Dixon et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10325948+8831489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH, <a href="#10" class="mim-tip-reference" title="Kong, W., Po, S., Yamagishi, T., Ashen, M. D., Stetten, G., Tomaselli, G. F. <strong>Isolation and characterization of the human gene encoding I(to): further diversity by alternative mRNA splicing.</strong> Am. J. Physiol. 275: H1963-H1970, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843794</a>] [<a href="https://doi.org/10.1152/ajpheart.1998.275.6.H1963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843794">Kong et al. (1998)</a> mapped the KCND3 gene to chromosome 1p13.3. By radiation hybrid mapping, <a href="#13" class="mim-tip-reference" title="Postma, A. V., Bezzina, C. R., de Vries, J. F., Wilde, A. A. M., Moorman, A. F. M., Mannens, M. M. A. M. <strong>Genomic organisation and chromosomal localisation of two members of the KCND ion channel family, KCND2 and KCND3.</strong> Hum. Genet. 106: 614-619, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942109</a>] [<a href="https://doi.org/10.1007/s004390000308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10942109">Postma et al. (2000)</a> assigned the gene to 1p13.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9843794+10942109" 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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In affected members of a Han Chinese family with spinocerebellar ataxia-19 (SCA19; <a href="/entry/607346">607346</a>), originally reported by <a href="#1" class="mim-tip-reference" title="Chung, M., Lu, Y.-C., Cheng, N.-C., Soong, B.-W. <strong>A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23.</strong> Brain 126: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12764052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12764052</a>] [<a href="https://doi.org/10.1093/brain/awg130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12764052">Chung et al. (2003)</a> as having SCA22, <a href="#12" class="mim-tip-reference" title="Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., and 10 others. <strong>Mutations in KCND3 cause spinocerebellar ataxia type 22.</strong> Ann. Neurol. 72: 859-869, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23280837[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/ana.23701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280837">Lee et al. (2012)</a> identified a heterozygous 3-bp deletion in the KCND3 gene (<a href="#0001">605411.0001</a>). The same heterozygous deletion was found in affected members of a French family with autosomal dominant SCA. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In HEK293 cells, the mutant protein showed no discernible cell surface expression and appeared to be abnormally retained within the endoplasmic reticulum. Voltage-clamp recordings showed decreased outward potassium currents compared to wildtype cells in response to voltage. Three additional heterozygous missense variants were found in the KCND3 gene (G345V, V338E, or T377M) in an Ashkenazi Jewish family and in 3 of 55 Japanese families with late-onset SCA, but segregation of the variants with the phenotype was unclear and no functional studies were performed on these variants. No KCND3 mutations were found in probands from 105 Chinese families with hereditary ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12764052+23280837" 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 SCA19, originally reported by <a href="#14" class="mim-tip-reference" title="Schelhaas, H. J., Ippel, P. F., Hageman, G., Sinke, R. J., van der Laan, E. N., Beemer, F. A. <strong>Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia.</strong> J. Neurol. 248: 113-120, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11284128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11284128</a>] [<a href="https://doi.org/10.1007/s004150170245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11284128">Schelhaas et al. (2001)</a>, <a href="#4" class="mim-tip-reference" title="Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S. <strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong> Ann. Neurol. 72: 870-880, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>] [<a href="https://doi.org/10.1002/ana.23700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280838">Duarri et al. (2012)</a> identified a heterozygous mutation in the KCND3 gene (T352P; <a href="#0002">605411.0002</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (<a href="/entry/604661">604661</a>). Patch-clamp recordings showed that the mutant channel had almost no detectable current activity (1% compared to wildtype). <a href="#4" class="mim-tip-reference" title="Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S. <strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong> Ann. Neurol. 72: 870-880, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>] [<a href="https://doi.org/10.1002/ana.23700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280838">Duarri et al. (2012)</a> suggested a dominant-negative effect and hypothesized that abnormal channel function may cause cellular toxicity due to abnormal intracellular calcium homeostasis, defects in long-term potentiation or depression, or chronic activation of the ER stress response. Two additional missense variants were identified in 2 probands, but segregation of the variants within the families was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23280838+11284128" 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 10-year-old boy with SCA19, <a href="#15" class="mim-tip-reference" title="Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., van de Warrenburg, B. P., Zuchner, S., Gonzalez, M. A., Schule, R., Synofzik, M., Van der Aa, N., De Jonghe, P., Verbeek, D. S., Baets, J. <strong>First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy.</strong> BMC Med. Genet. 16: 51, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26189493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26189493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26189493[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/10.1186/s12881-015-0200-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26189493">Smets et al. (2015)</a> identified a de novo heterozygous 9-bp duplication in the KCND3 gene (<a href="#0008">605411.0008</a>). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies to assess the effects of the duplication showed that the mutant protein was properly localized in the cell, but that it had significantly decreased protein stability. The mutation caused a strong shift in the voltage-dependence of activation and inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26189493" 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 16 patients from 2 unrelated French families with SCA19, <a href="#8" class="mim-tip-reference" title="Huin, V., Strubi-Vuillaume, I., Dujardin, K., Brion, M., Delliaux, M., Dellacherie, D., Cuvellier, J. C., Cuisset, J. M., Riquet, A., Moreau, C., Defebvre, L., Sablonniere, B., Devos, D. <strong>Expanding the phenotype of SCA19/22: parkinsonism, cognitive impairment and epilepsy.</strong> Parkinsonism Relat. Disord. 45: 85-89, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28947073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28947073</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2017.09.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28947073">Huin et al. (2017)</a> identified the 3-bp deletion in the KCND3 gene (<a href="#0001">605411.0001</a>) that had previously been reported by <a href="#12" class="mim-tip-reference" title="Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., and 10 others. <strong>Mutations in KCND3 cause spinocerebellar ataxia type 22.</strong> Ann. Neurol. 72: 859-869, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23280837[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/ana.23701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280837">Lee et al. (2012)</a>. In addition to typical features associated with SCA, 8 patients had mild parkinsonism and 5 had epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23280837+28947073" 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 30-year-old Japanese man with SCA19, <a href="#11" class="mim-tip-reference" title="Kurihara, M., Ishiura, H., Sasaki, T., Otsuka, J., Hayashi, T., Terao, Y., Matsukawa, T., Mitsui, J., Kaneko, J., Nishiyama, K., Doi, K., Yoshimura, J., Morishita, S., Shimizu, J., Tsuji, S. <strong>Novel de novo KCND3 mutation in a Japanese patient with intellectual disability, cerebellar ataxia, myoclonus, and dystonia.</strong> Cerebellum 17: 237-242, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28895081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28895081</a>] [<a href="https://doi.org/10.1007/s12311-017-0883-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28895081">Kurihara et al. (2018)</a> identified a de novo heterozygous missense mutation in the KCND3 gene (G384S; <a href="#0009">605411.0009</a>). The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or an in-house dataset of 800 healthy persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28895081" 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 screening of a Han Chinese cohort of patients with inherited cerebellar ataxias in Taiwan, <a href="#7" class="mim-tip-reference" title="Hsiao, C. T., Fu, S. J., Liu, Y. T., Lu, Y. H., Zhong, C. Y., Tang, C. Y., Soong, B. W., Jeng, C. J. <strong>Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.</strong> Hum. Mutat. 40: 2088-2107, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31293010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31293010</a>] [<a href="https://doi.org/10.1002/humu.23865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31293010">Hsiao et al. (2019)</a> identified 2 heterozygous variants in the KCND3 gene: a de novo c.950G-A transition in exon 2, resulting in a cys317-to-tyr (C317Y) substitution in 1 patient (pedigree A), and a c.1123C-T transition in exon 3, resulting in a pro375-to-ser (P375S) substitution in a mother and son (pedigree B). The authors then performed functional studies on these 2 mutations as well as on 2 previously reported missense mutations in the KCND3 gene. Electrophysiologic analyses showed that these mutations were associated with loss-of-function phenotypes. Additional studies showed that the mutations were associated with protein degradation and abnormal membrane trafficking. Coexpression of the wildtype with disease-related mutations provided evidence of dominant-negative effects of the mutations on protein biosynthesis and voltage-dependent gating of the Kv4.3 wildtype channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31293010" 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 9</em></strong></p><p>
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In a cohort of 86 patients with Brugada syndrome (see BRGDA9, <a href="/entry/616399">616399</a>) who were negative for mutation in 8 known Brugada-associated genes, <a href="#6" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Tester, D. J., Crotti, L., Mugione, A., Nesterenko, V. V., Albertson, R. M., Antzelevitch, C., Schwartz, P. J., Ackerman, M. J. <strong>Transient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.</strong> Heart Rhythm 8: 1024-1032, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21349352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21349352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21349352[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.hrthm.2011.02.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21349352">Giudicessi et al. (2011)</a> analyzed the candidate gene KCND3 and identified heterozygous missense mutations in 2 unrelated patients, L450F (<a href="#0005">605411.0005</a>) and G600R (<a href="#0006">605411.0006</a>). Functional analysis demonstrated that both variants were gain-of-function mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21349352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using DNA samples from 123 cases of sudden unexplained death that had already been screened for mutation in 7 major and 12 minor channelopathy-associated genes, <a href="#5" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J. <strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong> Hum. Mutat. 33: 989-997, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22457051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22457051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22457051[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/humu.22058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22457051">Giudicessi et al. (2012)</a> analyzed the KCND3 gene and identified heterozygosity for missense mutations in 2 cases, the G600R mutation in 1 case and a V392I mutation (<a href="#0007">605411.0007</a>) in the other. The V392I mutation was shown to be a gain-of-function change in functional studies, which also confirmed the gain-of-function nature of the G600R mutation. No KCND3 pathogenic variants were detected in 192 cases of sudden infant death syndrome (SIDS; see <a href="/entry/272120">272120</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22457051" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605411[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">rs397515475 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515475;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=rs397515475" 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=rs397515475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Han Chinese family with spinocerebellar ataxia-19 (SCA19; <a href="/entry/607346">607346</a>), originally reported by <a href="#1" class="mim-tip-reference" title="Chung, M., Lu, Y.-C., Cheng, N.-C., Soong, B.-W. <strong>A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23.</strong> Brain 126: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12764052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12764052</a>] [<a href="https://doi.org/10.1093/brain/awg130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12764052">Chung et al. (2003)</a>, <a href="#12" class="mim-tip-reference" title="Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., and 10 others. <strong>Mutations in KCND3 cause spinocerebellar ataxia type 22.</strong> Ann. Neurol. 72: 859-869, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23280837[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/ana.23701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280837">Lee et al. (2012)</a> identified a heterozygous 3-bp deletion (c.679_681delTTC) in the KCND3 gene, resulting in the deletion of residue Phe227, a highly conserved residue in the S2 transmembrane domain. The same heterozygous deletion was found in affected members of a French family with autosomal dominant SCA. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The mutation was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in 500 Taiwanese-Chinese controls, or in 152 French controls. In HEK293 cells, the mutant protein showed no discernible cell surface expression and appeared to be abnormally retained within the endoplasmic reticulum. Voltage-clamp recordings showed decreased outward potassium currents compared to wildtype cells in response to voltage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12764052+23280837" 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 16 patients from 2 unrelated French families with SCA19, <a href="#8" class="mim-tip-reference" title="Huin, V., Strubi-Vuillaume, I., Dujardin, K., Brion, M., Delliaux, M., Dellacherie, D., Cuvellier, J. C., Cuisset, J. M., Riquet, A., Moreau, C., Defebvre, L., Sablonniere, B., Devos, D. <strong>Expanding the phenotype of SCA19/22: parkinsonism, cognitive impairment and epilepsy.</strong> Parkinsonism Relat. Disord. 45: 85-89, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28947073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28947073</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2017.09.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28947073">Huin et al. (2017)</a> identified heterozygosity for the c.679_681delTTC mutation in the KCND3 gene. In addition to typical features associated with the disorder, 8 patients had mild parkinsonism and 5 had epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28947073" 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">rs397515476 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515476;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=rs397515476" 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=rs397515476" 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=RCV000056299 OR RCV001268855" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056299, RCV001268855" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056299...</a>
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<p>In affected members of a large Dutch family with spinocerebellar ataxia-19 (SCA19; <a href="/entry/607346">607346</a>), originally reported by <a href="#14" class="mim-tip-reference" title="Schelhaas, H. J., Ippel, P. F., Hageman, G., Sinke, R. J., van der Laan, E. N., Beemer, F. A. <strong>Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia.</strong> J. Neurol. 248: 113-120, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11284128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11284128</a>] [<a href="https://doi.org/10.1007/s004150170245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11284128">Schelhaas et al. (2001)</a>, <a href="#4" class="mim-tip-reference" title="Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S. <strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong> Ann. Neurol. 72: 870-880, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>] [<a href="https://doi.org/10.1002/ana.23700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280838">Duarri et al. (2012)</a> identified a heterozygous c.1054A-C transversion in the KCND3 gene, resulting in a thr352-to-pro (T352P) substitution at a highly conserved residue in the third extracellular loop. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. Cerebellar tissue from 1 affected individual showed intense KCND3 staining within large puncta in the soma of Purkinje cells. Transfection of the mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (<a href="/entry/604661">604661</a>). Patch-clamp recordings showed that the mutant channel had almost no detectable current activity (1% compared to wildtype). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23280838+11284128" 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">rs397515477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515477;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=rs397515477" 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=rs397515477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant is classified as a variant of unknown significance because its contribution to spinocerebellar ataxia-19 (<a href="/entry/607346">607346</a>) has not been confirmed.</p><p>In a Dutch father and daughter with late-onset spinocerebellar ataxia, <a href="#4" class="mim-tip-reference" title="Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S. <strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong> Ann. Neurol. 72: 870-880, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>] [<a href="https://doi.org/10.1002/ana.23700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280838">Duarri et al. (2012)</a> identified a heterozygous c.1119G-A transition in the KCND3 gene, resulting in a met373-to-ile (M373I) substitution at a highly conserved residue. The mutation was initially found by direct sequencing of the KCND3 gene in 230 Dutch probands with ataxia in whom mutations in several known SCA genes were not identified. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. The proband had ambiguous neurologic signs on testing at age 44 years, and later had no neurologic signs at age 52 years, consistent with being an asymptomatic carrier. He had a relevant family history, with both his father and a sister showing signs of the disorder. His father was more severely affected, with onset of progressive ataxic gait at age 55 years, dysarthria, and cerebellar atrophy on brain MRI. His sister had very mild gait impairment at age 64 years. Transfection of the M373I mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (<a href="/entry/604661">604661</a>). Patch-clamp recordings showed that the mutant channel had decreased current activity (25% of controls). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23280838" 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">rs397515478 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515478;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=rs397515478" 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=rs397515478" 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=RCV000056301 OR RCV001849175" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056301, RCV001849175" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056301...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to spinocerebellar ataxia-19 (<a href="/entry/607346">607346</a>) has not been confirmed.</p><p>In a Dutch man with slowly progressive spinocerebellar ataxia with onset at age 30 years, <a href="#4" class="mim-tip-reference" title="Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S. <strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong> Ann. Neurol. 72: 870-880, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>] [<a href="https://doi.org/10.1002/ana.23700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280838">Duarri et al. (2012)</a> identified a heterozygous c.1169G-A transition in the KCND3 gene, resulting in a ser390-to-asn (S390N) substitution at a highly conserved residue. The mutation was found by direct sequencing of the KCND3 gene in 230 Dutch probands with ataxia in whom mutations in several known SCA genes were not identified. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. The patient had spastic ataxia, dysarthria, saccadic eye movements, nystagmus, cognitive impairment, hearing deficits, and cerebellar atrophy on brain imaging. The patient's mother and brother were diagnosed with a similar disorder, but genetic material was not available from them to confirm cosegregation of the S390N variant with the disorder. Transfection of the S390N mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects were unable to be rescued by coexpression with the active isoform of KCHIP2 (<a href="/entry/604661">604661</a>). Patch-clamp recordings showed that the mutant channel had decreased current activity (13% of controls). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23280838" 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> rs150401343 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150401343;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/rs150401343?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=rs150401343" 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=rs150401343" 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=RCV000172842 OR RCV000415916 OR RCV000552635 OR RCV000618307 OR RCV002247580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000172842, RCV000415916, RCV000552635, RCV000618307, RCV002247580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000172842...</a>
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<p>In a 45-year-old man with Brugada syndrome (BRGDA9; <a href="/entry/616399">616399</a>), <a href="#6" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Tester, D. J., Crotti, L., Mugione, A., Nesterenko, V. V., Albertson, R. M., Antzelevitch, C., Schwartz, P. J., Ackerman, M. J. <strong>Transient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.</strong> Heart Rhythm 8: 1024-1032, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21349352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21349352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21349352[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.hrthm.2011.02.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21349352">Giudicessi et al. (2011)</a> identified heterozygosity for a c.348C-T transition in the KCND3 gene, resulting in a leu450-to-phe (L450F) substitution at a highly conserved residue in the Kv4.3 carboxyl C terminus. The mutation was not found in 1,560 reference alleles. Functional analysis in HEK293 cells showed significantly increased transient outward current density at 0 mV and at 40 mV with the L450F mutant, by 154.3% and 146.2% over wildtype. In addition, the L450F mutant significantly increased the total charge of the transient outward current at 40 mV, by 117% over wildtype, and significantly shifted inactivation kinetics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21349352" 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="You, T., Mao, W., Cai, B., Li, F., Xu, H. <strong>Two novel Brugada syndrome-associated mutations increase Kv4.3 membrane expression and function.</strong> Int. J. Molec. Med. 36: 309-315, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26016905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26016905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26016905[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/10.3892/ijmm.2015.2223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26016905">You et al. (2015)</a> generated rat Kv4.3 with either a G581R or L450F mutation, corresponding to the human G600R (<a href="#0006">605411.0006</a>) and L450F mutations associated with Brugada syndrome, respectively. Expression of mutant Kv4.3 with Kchip2 in HEK293 cells showed that the mutants caused a gain of function of the transient outward K+ currents, as the mutants increased Kv4.3 protein expression and influenced the kinetics of the transient outward K+ currents by slowing down channel inactivation. Furthermore, the Kv4.3 mutants enhanced membrane localization of the Kv4.3 protein, but they did not affect the mRNA level of Kv4.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26016905" 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> rs149344567 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149344567;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/rs149344567?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=rs149344567" 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=rs149344567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 22-year-old man with Brugada syndrome (BRGDA9; <a href="/entry/616399">616399</a>), <a href="#6" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Tester, D. J., Crotti, L., Mugione, A., Nesterenko, V. V., Albertson, R. M., Antzelevitch, C., Schwartz, P. J., Ackerman, M. J. <strong>Transient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.</strong> Heart Rhythm 8: 1024-1032, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21349352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21349352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21349352[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.hrthm.2011.02.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21349352">Giudicessi et al. (2011)</a> identified heterozygosity for a c.1798G-C transversion (later reported by <a href="#5" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J. <strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong> Hum. Mutat. 33: 989-997, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22457051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22457051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22457051[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/humu.22058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22457051">Giudicessi et al. (2012)</a> as a c.1798G-A transition) in the KCND3 gene, resulting in a gly600-to-arg (G600R) substitution at a highly conserved residue in the Kv4.3 C terminus. The mutation was not found in 1,560 reference alleles. Functional analysis in HEK293 cells showed significantly increased transient outward current density at 0 mV and at 40 mV with the G600R mutant, by 48.1% and 50.4% over wildtype. In addition, the G600R mutant exhibited significantly slower inactivation across the 0 to 40 mV range and a significantly increased total charge of the transient outward current at 40 mV compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21349352+22457051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using DNA from a 23-year-old asymptomatic male athlete who died from cardiopulmonary arrest while swimming laps, <a href="#5" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J. <strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong> Hum. Mutat. 33: 989-997, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22457051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22457051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22457051[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/humu.22058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22457051">Giudicessi et al. (2012)</a> identified heterozygosity for the G600R substitution in the KCND3 gene. The variant (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149344567;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs149344567</a>) was not found in 1,560 reference alleles or in the 1000 Genomes Project database; it was found in a single individual in the dbSNP (build 134) database. Premortem electrocardiograms (ECGs) from the proband were unavailable. There was no family history of sudden unexplained death, and screening ECGs in his parents and sister were reportedly normal. Family members declined to provide DNA for genetic testing. Functional analysis in HEK293 cells confirmed the marked gain-of-function electrophysiologic phenotype with the G600R variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22457051" 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="You, T., Mao, W., Cai, B., Li, F., Xu, H. <strong>Two novel Brugada syndrome-associated mutations increase Kv4.3 membrane expression and function.</strong> Int. J. Molec. Med. 36: 309-315, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26016905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26016905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26016905[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/10.3892/ijmm.2015.2223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26016905">You et al. (2015)</a> generated rat Kv4.3 with either a G581R or L450F mutation, corresponding to the human G600R and L450F (<a href="#0005">605411.0005</a>) mutations associated with Brugada syndrome, respectively. Expression of mutant Kv4.3 with Kchip2 in HEK293 cells showed that the mutants caused a gain of function of the transient outward K+ currents, as the mutants increased Kv4.3 protein expression and influenced the kinetics of the transient outward K+ currents by slowing down channel inactivation. Furthermore, the Kv4.3 mutants enhanced membrane localization of the Kv4.3 protein, but they did not affect the mRNA level of Kv4.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26016905" 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">rs786205867 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205867;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=rs786205867" 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=rs786205867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a DNA sample from a 20-year-old man with a history of syncopal episodes who was found unresponsive in bed and could not be resuscitated (BRGDA9; <a href="/entry/616399">616399</a>), <a href="#5" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J. <strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong> Hum. Mutat. 33: 989-997, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22457051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22457051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22457051[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/humu.22058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22457051">Giudicessi et al. (2012)</a> identified heterozygosity for a c.1174G-A transition in the KCND3 gene, resulting in a val392-to-ile (V392I) substitution at a conserved residue. The variant was not found in 1,560 reference alleles or in the 1000 Genomes Project or dbSNP (build 134) databases. Premortem electrocardiograms (ECGs) from the proband were unavailable, and family members declined to participate in the study. Functional analysis in HEK293 cells demonstrated that the V392I-mutant Kv4.3 channel dramatically increases both peak transient outward current density (100.4%) and total charge (298.7%), while slowing decay time (138%), indicating a gain of function. However, the V392I mutant also slows the recovery from inactivation (360.9%), suggesting a mixed electrophysiologic phenotype. <a href="#5" class="mim-tip-reference" title="Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J. <strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong> Hum. Mutat. 33: 989-997, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22457051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22457051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22457051[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/humu.22058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22457051">Giudicessi et al. (2012)</a> stated that this patient's death during sleep was consistent with a Brugada syndrome-like gain of function as the primary underlying etiology, with a Brugada syndrome-triggered fatal arrhythmia as the chief arrhythmia phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22457051" 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 10-year-old boy with spinocerebellar ataxia-19 (SCA19; <a href="/entry/607346">607346</a>), <a href="#15" class="mim-tip-reference" title="Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., van de Warrenburg, B. P., Zuchner, S., Gonzalez, M. A., Schule, R., Synofzik, M., Van der Aa, N., De Jonghe, P., Verbeek, D. S., Baets, J. <strong>First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy.</strong> BMC Med. Genet. 16: 51, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26189493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26189493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26189493[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/10.1186/s12881-015-0200-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26189493">Smets et al. (2015)</a> identified a de novo heterozygous 9-bp duplication (c.877_885dupCGCGTCTTC, NM_004980.4) in the KCND3 gene, resulting in a 3-amino acid duplication (Arg293_Phe295dup) of the RVF (Arg-Val-Phe) domain in the S4 segment of Kv4.3. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. Studies to assess the effects of the duplication showed that the mutant protein was properly localized in the cell, but that it had significantly decreased stability. The mutation caused a strong shift in the voltage-dependence of activation and inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26189493" 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>.0009 SPINOCEREBELLAR ATAXIA 19</strong>
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KCND3, GLY384SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1664632655 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1664632655;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=rs1664632655" 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=rs1664632655" 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=RCV001289013 OR RCV003389334 OR RCV004629532" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001289013, RCV003389334, RCV004629532" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001289013...</a>
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<p>In a 30-year-old Japanese man with spinocerebellar ataxia-19 (SCA19; <a href="/entry/607346">607346</a>), <a href="#11" class="mim-tip-reference" title="Kurihara, M., Ishiura, H., Sasaki, T., Otsuka, J., Hayashi, T., Terao, Y., Matsukawa, T., Mitsui, J., Kaneko, J., Nishiyama, K., Doi, K., Yoshimura, J., Morishita, S., Shimizu, J., Tsuji, S. <strong>Novel de novo KCND3 mutation in a Japanese patient with intellectual disability, cerebellar ataxia, myoclonus, and dystonia.</strong> Cerebellum 17: 237-242, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28895081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28895081</a>] [<a href="https://doi.org/10.1007/s12311-017-0883-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28895081">Kurihara et al. (2018)</a> identified a de novo heterozygous c.1150G-A transition in the KCND3 gene, resulting in a gly384-to-ser (G384S) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or an in-house dataset of 800 healthy persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28895081" 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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Chung, M., Lu, Y.-C., Cheng, N.-C., Soong, B.-W.
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<strong>A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23.</strong>
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[<a href="https://doi.org/10.1093/brain/awg130" target="_blank">Full Text</a>]
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Dilks, D., Ling, H.-P., Cockett, M., Sokol, P., Numann, R.
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<strong>Cloning and expression of the human Kv4.3 potassium channel.</strong>
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[<a href="https://doi.org/10.1152/jn.1999.81.4.1974" target="_blank">Full Text</a>]
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Dixon, J. E., Shi, W., Wang, H.-S., McDonald, C., Yu, H., Wymore, R. S., Cohen, I. S., McKinnon, D.
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<strong>Role of the Kv4.3 K+ channel in ventricular muscle: a molecular correlate for the transient outward current.</strong>
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Circ. Res. 79: 659-668, 1996. Note: Erratum: Circ. Res. 80: 147 only, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8831489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8831489</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8831489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.res.79.4.659" target="_blank">Full Text</a>]
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Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S.
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<strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong>
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Ann. Neurol. 72: 870-880, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280838</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23280838" 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/ana.23700" target="_blank">Full Text</a>]
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Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J.
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<strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong>
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Hum. Mutat. 33: 989-997, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22457051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22457051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22457051[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=22457051" 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/humu.22058" target="_blank">Full Text</a>]
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Giudicessi, J. R., Ye, D., Tester, D. J., Crotti, L., Mugione, A., Nesterenko, V. V., Albertson, R. M., Antzelevitch, C., Schwartz, P. J., Ackerman, M. J.
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<strong>Transient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.</strong>
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Heart Rhythm 8: 1024-1032, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21349352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21349352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21349352[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=21349352" 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.hrthm.2011.02.021" target="_blank">Full Text</a>]
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<a id="Hsiao2019" class="mim-anchor"></a>
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Hsiao, C. T., Fu, S. J., Liu, Y. T., Lu, Y. H., Zhong, C. Y., Tang, C. Y., Soong, B. W., Jeng, C. J.
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<strong>Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.</strong>
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Hum. Mutat. 40: 2088-2107, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31293010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31293010</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31293010" 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/humu.23865" target="_blank">Full Text</a>]
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<a id="Huin2017" class="mim-anchor"></a>
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Huin, V., Strubi-Vuillaume, I., Dujardin, K., Brion, M., Delliaux, M., Dellacherie, D., Cuvellier, J. C., Cuisset, J. M., Riquet, A., Moreau, C., Defebvre, L., Sablonniere, B., Devos, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28947073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28947073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28947073" 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.parkreldis.2017.09.014" target="_blank">Full Text</a>]
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Isbrandt, D., Leicher, T., Waldschutz, R., Zhu, X., Luhmann, U., Michel, U., Sauter, K., Pongs, O.
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<strong>Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(to) and I(sa).</strong>
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Genomics 64: 144-154, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10729221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10729221</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10729221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.2000.6117" target="_blank">Full Text</a>]
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Kong, W., Po, S., Yamagishi, T., Ashen, M. D., Stetten, G., Tomaselli, G. F.
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<strong>Isolation and characterization of the human gene encoding I(to): further diversity by alternative mRNA splicing.</strong>
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Am. J. Physiol. 275: H1963-H1970, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843794</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843794" 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/10.1152/ajpheart.1998.275.6.H1963" target="_blank">Full Text</a>]
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<a id="Kurihara2018" class="mim-anchor"></a>
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Kurihara, M., Ishiura, H., Sasaki, T., Otsuka, J., Hayashi, T., Terao, Y., Matsukawa, T., Mitsui, J., Kaneko, J., Nishiyama, K., Doi, K., Yoshimura, J., Morishita, S., Shimizu, J., Tsuji, S.
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<strong>Novel de novo KCND3 mutation in a Japanese patient with intellectual disability, cerebellar ataxia, myoclonus, and dystonia.</strong>
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Cerebellum 17: 237-242, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28895081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28895081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28895081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s12311-017-0883-4" target="_blank">Full Text</a>]
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</p>
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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="Lee2012" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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|
Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., and 10 others.
|
|
<strong>Mutations in KCND3 cause spinocerebellar ataxia type 22.</strong>
|
|
Ann. Neurol. 72: 859-869, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23280837[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=23280837" 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/ana.23701" 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="13" class="mim-anchor"></a>
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<a id="Postma2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Postma, A. V., Bezzina, C. R., de Vries, J. F., Wilde, A. A. M., Moorman, A. F. M., Mannens, M. M. A. M.
|
|
<strong>Genomic organisation and chromosomal localisation of two members of the KCND ion channel family, KCND2 and KCND3.</strong>
|
|
Hum. Genet. 106: 614-619, 2000.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942109</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390000308" 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="Schelhaas2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Schelhaas, H. J., Ippel, P. F., Hageman, G., Sinke, R. J., van der Laan, E. N., Beemer, F. A.
|
|
<strong>Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia.</strong>
|
|
J. Neurol. 248: 113-120, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11284128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11284128</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11284128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004150170245" 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="Smets2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., van de Warrenburg, B. P., Zuchner, S., Gonzalez, M. A., Schule, R., Synofzik, M., Van der Aa, N., De Jonghe, P., Verbeek, D. S., Baets, J.
|
|
<strong>First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy.</strong>
|
|
BMC Med. Genet. 16: 51, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26189493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26189493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26189493[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=26189493" 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/10.1186/s12881-015-0200-3" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Tseng1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tseng, G.-N.
|
|
<strong>Molecular structure of cardiac I(to) channels: Kv4.2, Kv4.3, and other possibilities?</strong>
|
|
Cardiovasc. Res. 41: 16-18, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10325948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10325948</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10325948" 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/s0008-6363(98)00282-x" 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="You2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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You, T., Mao, W., Cai, B., Li, F., Xu, H.
|
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<strong>Two novel Brugada syndrome-associated mutations increase Kv4.3 membrane expression and function.</strong>
|
|
Int. J. Molec. Med. 36: 309-315, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26016905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26016905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26016905[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=26016905" 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/10.3892/ijmm.2015.2223" 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="Zhu1999" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Zhu, X. R., Wulf, A., Schwarz, M., Isbrandt, D., Pongs, O.
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<strong>Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current.</strong>
|
|
Receptors Channels 6: 387-400, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10551270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10551270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10551270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</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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Sonja A. Rasmussen - updated : 11/07/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 06/29/2023<br>Marla J. F. O'Neill - updated : 5/29/2015<br>Cassandra L. Kniffin - updated : 10/7/2013<br>Victor A. McKusick - updated : 11/20/2000
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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="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 11/20/2000
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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 : 11/08/2023
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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">
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carol : 11/07/2023<br>mgross : 06/29/2023<br>carol : 04/12/2017<br>carol : 06/03/2015<br>mcolton : 5/29/2015<br>carol : 10/8/2013<br>carol : 10/8/2013<br>ckniffin : 10/7/2013<br>terry : 11/29/2012<br>carol : 12/23/2002<br>terry : 1/19/2001<br>terry : 1/19/2001<br>carol : 11/20/2000
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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 class="container visible-print-block">
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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">
|
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<strong>*</strong> 605411
|
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</span>
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</h3>
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
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|
|
POTASSIUM VOLTAGE-GATED CHANNEL, SHAL-RELATED SUBFAMILY, MEMBER 3; KCND3
|
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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-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
Kv4.3<br />
|
|
KCND3S
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<span class="h3 mim-font">
|
|
KCND3L, INCLUDED
|
|
</span>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: KCND3</em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
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|
|
<strong>SNOMEDCT:</strong> 719251009;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 1p13.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:111,770,662-111,989,668 </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>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
1p13.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Brugada syndrome 9
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616399
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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|
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|
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</tr>
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|
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|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 19
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607346
|
|
</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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</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>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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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 class="mim-text-font">
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<p>The KCND3 gene encodes Kv4.3, an alpha subunit of the Shal family of A-type voltage-gated potassium channels, which are important in membrane repolarization in excitable cells (summary by Lee et al., 2012). </p>
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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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</h4>
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<span class="mim-text-font">
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<p>By screening a cardiac cDNA library and RT-PCR of human ventricular RNA, Kong et al. (1998) isolated a cDNA encoding KCND3. The deduced 637-amino acid protein shares 99% sequence homology with the rat homolog. KCND3 contains 6 transmembrane segments and intracellular N- and C-termini. RT-PCR and sequence analysis demonstrated the existence of a splice variant, KCND3L, with an insert encoding an additional 19 amino acids and containing a phosphorylation site. The shorter isoform was designated KCND3S. Zhu et al. (1999) found that the KCND3L, KCND1 (300281), and KCND2 (605410) proteins share 60% sequence identity and 71% homology, with the least conservation in the C terminus. By Northern blot analysis, Kong et al. (1998) detected expression of an 8.5-kb transcript that is most abundant in brain and heart and is not detectable in kidney, liver, lung, pancreas, spleen, or skeletal muscle. By the same method, Isbrandt et al. (2000) found that expression within the brain is greatest in the cerebral cortex. By RT-PCR analysis, they found that the long transcript predominates in thalamus, caudate nucleus, white matter, and epiphysis, whereas the short transcript is more abundant in frontal cortex, occipital lobe, and cerebellar cortex. Dilks et al. (1999), who cloned KCND3 from human heart and brain, found by RT-PCR that only the long form of KCND3 is expressed in heart. Isbrandt et al. (2000) determined that the long form of the KCND3 gene contains 7 exons and spans at least 25 kb. The shorter isoform is encoded by 6 exons. Kong et al. (1998) and Dilks et al. (1999) found no differences in the splice variants in terms of their voltage dependence or inactivation kinetics in the basal state. </p><p>In human cerebellar tissue, Duarri et al. (2012) found weak, punctuated immunostaining for the KCND3 gene in Purkinje cell bodies. </p>
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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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<span class="mim-text-font">
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<p>The transient outward potassium current, I(to), is especially important during the early phase of repolarization in many species, including human, as it sets the plateau voltage of both the atrial and the ventricular action potential. KCND2 and/or KCND3 code for the primary alpha subunits responsible for I(to) (Tseng, 1999). In the human ventricle, KCND3 is the gene that encodes the K+ channel that underlies I(to) (Dixon et al., 1996). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By FISH, Kong et al. (1998) mapped the KCND3 gene to chromosome 1p13.3. By radiation hybrid mapping, Postma et al. (2000) assigned the gene to 1p13.2. </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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<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>Spinocerebellar Ataxia 19</em></strong></p><p>
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In affected members of a Han Chinese family with spinocerebellar ataxia-19 (SCA19; 607346), originally reported by Chung et al. (2003) as having SCA22, Lee et al. (2012) identified a heterozygous 3-bp deletion in the KCND3 gene (605411.0001). The same heterozygous deletion was found in affected members of a French family with autosomal dominant SCA. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In HEK293 cells, the mutant protein showed no discernible cell surface expression and appeared to be abnormally retained within the endoplasmic reticulum. Voltage-clamp recordings showed decreased outward potassium currents compared to wildtype cells in response to voltage. Three additional heterozygous missense variants were found in the KCND3 gene (G345V, V338E, or T377M) in an Ashkenazi Jewish family and in 3 of 55 Japanese families with late-onset SCA, but segregation of the variants with the phenotype was unclear and no functional studies were performed on these variants. No KCND3 mutations were found in probands from 105 Chinese families with hereditary ataxia. </p><p>In affected members of a large Dutch family with SCA19, originally reported by Schelhaas et al. (2001), Duarri et al. (2012) identified a heterozygous mutation in the KCND3 gene (T352P; 605411.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (604661). Patch-clamp recordings showed that the mutant channel had almost no detectable current activity (1% compared to wildtype). Duarri et al. (2012) suggested a dominant-negative effect and hypothesized that abnormal channel function may cause cellular toxicity due to abnormal intracellular calcium homeostasis, defects in long-term potentiation or depression, or chronic activation of the ER stress response. Two additional missense variants were identified in 2 probands, but segregation of the variants within the families was unclear. </p><p>In a 10-year-old boy with SCA19, Smets et al. (2015) identified a de novo heterozygous 9-bp duplication in the KCND3 gene (605411.0008). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies to assess the effects of the duplication showed that the mutant protein was properly localized in the cell, but that it had significantly decreased protein stability. The mutation caused a strong shift in the voltage-dependence of activation and inactivation. </p><p>In 16 patients from 2 unrelated French families with SCA19, Huin et al. (2017) identified the 3-bp deletion in the KCND3 gene (605411.0001) that had previously been reported by Lee et al. (2012). In addition to typical features associated with SCA, 8 patients had mild parkinsonism and 5 had epilepsy. </p><p>In a 30-year-old Japanese man with SCA19, Kurihara et al. (2018) identified a de novo heterozygous missense mutation in the KCND3 gene (G384S; 605411.0009). The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or an in-house dataset of 800 healthy persons. </p><p>By screening of a Han Chinese cohort of patients with inherited cerebellar ataxias in Taiwan, Hsiao et al. (2019) identified 2 heterozygous variants in the KCND3 gene: a de novo c.950G-A transition in exon 2, resulting in a cys317-to-tyr (C317Y) substitution in 1 patient (pedigree A), and a c.1123C-T transition in exon 3, resulting in a pro375-to-ser (P375S) substitution in a mother and son (pedigree B). The authors then performed functional studies on these 2 mutations as well as on 2 previously reported missense mutations in the KCND3 gene. Electrophysiologic analyses showed that these mutations were associated with loss-of-function phenotypes. Additional studies showed that the mutations were associated with protein degradation and abnormal membrane trafficking. Coexpression of the wildtype with disease-related mutations provided evidence of dominant-negative effects of the mutations on protein biosynthesis and voltage-dependent gating of the Kv4.3 wildtype channel. </p><p><strong><em>Brugada Syndrome 9</em></strong></p><p>
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In a cohort of 86 patients with Brugada syndrome (see BRGDA9, 616399) who were negative for mutation in 8 known Brugada-associated genes, Giudicessi et al. (2011) analyzed the candidate gene KCND3 and identified heterozygous missense mutations in 2 unrelated patients, L450F (605411.0005) and G600R (605411.0006). Functional analysis demonstrated that both variants were gain-of-function mutations. </p><p>Using DNA samples from 123 cases of sudden unexplained death that had already been screened for mutation in 7 major and 12 minor channelopathy-associated genes, Giudicessi et al. (2012) analyzed the KCND3 gene and identified heterozygosity for missense mutations in 2 cases, the G600R mutation in 1 case and a V392I mutation (605411.0007) in the other. The V392I mutation was shown to be a gain-of-function change in functional studies, which also confirmed the gain-of-function nature of the G600R mutation. No KCND3 pathogenic variants were detected in 192 cases of sudden infant death syndrome (SIDS; see 272120). </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 SPINOCEREBELLAR ATAXIA 19</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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KCND3, 3-BP DEL, 679TTC
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<br />
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SNP: rs397515475,
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ClinVar: RCV000056298, RCV001268494
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Han Chinese family with spinocerebellar ataxia-19 (SCA19; 607346), originally reported by Chung et al. (2003), Lee et al. (2012) identified a heterozygous 3-bp deletion (c.679_681delTTC) in the KCND3 gene, resulting in the deletion of residue Phe227, a highly conserved residue in the S2 transmembrane domain. The same heterozygous deletion was found in affected members of a French family with autosomal dominant SCA. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The mutation was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in 500 Taiwanese-Chinese controls, or in 152 French controls. In HEK293 cells, the mutant protein showed no discernible cell surface expression and appeared to be abnormally retained within the endoplasmic reticulum. Voltage-clamp recordings showed decreased outward potassium currents compared to wildtype cells in response to voltage. </p><p>In 16 patients from 2 unrelated French families with SCA19, Huin et al. (2017) identified heterozygosity for the c.679_681delTTC mutation in the KCND3 gene. In addition to typical features associated with the disorder, 8 patients had mild parkinsonism and 5 had epilepsy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPINOCEREBELLAR ATAXIA 19</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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KCND3, THR352PRO
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<br />
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SNP: rs397515476,
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ClinVar: RCV000056299, RCV001268855
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large Dutch family with spinocerebellar ataxia-19 (SCA19; 607346), originally reported by Schelhaas et al. (2001), Duarri et al. (2012) identified a heterozygous c.1054A-C transversion in the KCND3 gene, resulting in a thr352-to-pro (T352P) substitution at a highly conserved residue in the third extracellular loop. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. Cerebellar tissue from 1 affected individual showed intense KCND3 staining within large puncta in the soma of Purkinje cells. Transfection of the mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (604661). Patch-clamp recordings showed that the mutant channel had almost no detectable current activity (1% compared to wildtype). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCND3, MET373ILE
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<br />
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SNP: rs397515477,
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ClinVar: RCV000056300
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant is classified as a variant of unknown significance because its contribution to spinocerebellar ataxia-19 (607346) has not been confirmed.</p><p>In a Dutch father and daughter with late-onset spinocerebellar ataxia, Duarri et al. (2012) identified a heterozygous c.1119G-A transition in the KCND3 gene, resulting in a met373-to-ile (M373I) substitution at a highly conserved residue. The mutation was initially found by direct sequencing of the KCND3 gene in 230 Dutch probands with ataxia in whom mutations in several known SCA genes were not identified. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. The proband had ambiguous neurologic signs on testing at age 44 years, and later had no neurologic signs at age 52 years, consistent with being an asymptomatic carrier. He had a relevant family history, with both his father and a sister showing signs of the disorder. His father was more severely affected, with onset of progressive ataxic gait at age 55 years, dysarthria, and cerebellar atrophy on brain MRI. His sister had very mild gait impairment at age 64 years. Transfection of the M373I mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (604661). Patch-clamp recordings showed that the mutant channel had decreased current activity (25% of 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>.0004 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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KCND3, SER390ASN
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<br />
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SNP: rs397515478,
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ClinVar: RCV000056301, RCV001849175
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant is classified as a variant of unknown significance because its contribution to spinocerebellar ataxia-19 (607346) has not been confirmed.</p><p>In a Dutch man with slowly progressive spinocerebellar ataxia with onset at age 30 years, Duarri et al. (2012) identified a heterozygous c.1169G-A transition in the KCND3 gene, resulting in a ser390-to-asn (S390N) substitution at a highly conserved residue. The mutation was found by direct sequencing of the KCND3 gene in 230 Dutch probands with ataxia in whom mutations in several known SCA genes were not identified. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. The patient had spastic ataxia, dysarthria, saccadic eye movements, nystagmus, cognitive impairment, hearing deficits, and cerebellar atrophy on brain imaging. The patient's mother and brother were diagnosed with a similar disorder, but genetic material was not available from them to confirm cosegregation of the S390N variant with the disorder. Transfection of the S390N mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects were unable to be rescued by coexpression with the active isoform of KCHIP2 (604661). Patch-clamp recordings showed that the mutant channel had decreased current activity (13% of 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>.0005 BRUGADA SYNDROME 9</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCND3, LEU450PHE
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<br />
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SNP: rs150401343,
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gnomAD: rs150401343,
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ClinVar: RCV000172842, RCV000415916, RCV000552635, RCV000618307, RCV002247580
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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 45-year-old man with Brugada syndrome (BRGDA9; 616399), Giudicessi et al. (2011) identified heterozygosity for a c.348C-T transition in the KCND3 gene, resulting in a leu450-to-phe (L450F) substitution at a highly conserved residue in the Kv4.3 carboxyl C terminus. The mutation was not found in 1,560 reference alleles. Functional analysis in HEK293 cells showed significantly increased transient outward current density at 0 mV and at 40 mV with the L450F mutant, by 154.3% and 146.2% over wildtype. In addition, the L450F mutant significantly increased the total charge of the transient outward current at 40 mV, by 117% over wildtype, and significantly shifted inactivation kinetics. </p><p>You et al. (2015) generated rat Kv4.3 with either a G581R or L450F mutation, corresponding to the human G600R (605411.0006) and L450F mutations associated with Brugada syndrome, respectively. Expression of mutant Kv4.3 with Kchip2 in HEK293 cells showed that the mutants caused a gain of function of the transient outward K+ currents, as the mutants increased Kv4.3 protein expression and influenced the kinetics of the transient outward K+ currents by slowing down channel inactivation. Furthermore, the Kv4.3 mutants enhanced membrane localization of the Kv4.3 protein, but they did not affect the mRNA level of Kv4.3. </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 BRUGADA SYNDROME 9</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCND3, GLY600ARG ({dbSNP rs149344567})
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<br />
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SNP: rs149344567,
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gnomAD: rs149344567,
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ClinVar: RCV000172843, RCV000619002, RCV000712060, RCV001370775, RCV002505242
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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 22-year-old man with Brugada syndrome (BRGDA9; 616399), Giudicessi et al. (2011) identified heterozygosity for a c.1798G-C transversion (later reported by Giudicessi et al. (2012) as a c.1798G-A transition) in the KCND3 gene, resulting in a gly600-to-arg (G600R) substitution at a highly conserved residue in the Kv4.3 C terminus. The mutation was not found in 1,560 reference alleles. Functional analysis in HEK293 cells showed significantly increased transient outward current density at 0 mV and at 40 mV with the G600R mutant, by 48.1% and 50.4% over wildtype. In addition, the G600R mutant exhibited significantly slower inactivation across the 0 to 40 mV range and a significantly increased total charge of the transient outward current at 40 mV compared to wildtype. </p><p>Using DNA from a 23-year-old asymptomatic male athlete who died from cardiopulmonary arrest while swimming laps, Giudicessi et al. (2012) identified heterozygosity for the G600R substitution in the KCND3 gene. The variant (rs149344567) was not found in 1,560 reference alleles or in the 1000 Genomes Project database; it was found in a single individual in the dbSNP (build 134) database. Premortem electrocardiograms (ECGs) from the proband were unavailable. There was no family history of sudden unexplained death, and screening ECGs in his parents and sister were reportedly normal. Family members declined to provide DNA for genetic testing. Functional analysis in HEK293 cells confirmed the marked gain-of-function electrophysiologic phenotype with the G600R variant. </p><p>You et al. (2015) generated rat Kv4.3 with either a G581R or L450F mutation, corresponding to the human G600R and L450F (605411.0005) mutations associated with Brugada syndrome, respectively. Expression of mutant Kv4.3 with Kchip2 in HEK293 cells showed that the mutants caused a gain of function of the transient outward K+ currents, as the mutants increased Kv4.3 protein expression and influenced the kinetics of the transient outward K+ currents by slowing down channel inactivation. Furthermore, the Kv4.3 mutants enhanced membrane localization of the Kv4.3 protein, but they did not affect the mRNA level of Kv4.3. </p>
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<h4>
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<span class="mim-font">
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<strong>.0007 BRUGADA SYNDROME 9</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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KCND3, VAL392ILE
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<br />
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SNP: rs786205867,
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ClinVar: RCV000172844, RCV000444260, RCV000460804
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<p>In a DNA sample from a 20-year-old man with a history of syncopal episodes who was found unresponsive in bed and could not be resuscitated (BRGDA9; 616399), Giudicessi et al. (2012) identified heterozygosity for a c.1174G-A transition in the KCND3 gene, resulting in a val392-to-ile (V392I) substitution at a conserved residue. The variant was not found in 1,560 reference alleles or in the 1000 Genomes Project or dbSNP (build 134) databases. Premortem electrocardiograms (ECGs) from the proband were unavailable, and family members declined to participate in the study. Functional analysis in HEK293 cells demonstrated that the V392I-mutant Kv4.3 channel dramatically increases both peak transient outward current density (100.4%) and total charge (298.7%), while slowing decay time (138%), indicating a gain of function. However, the V392I mutant also slows the recovery from inactivation (360.9%), suggesting a mixed electrophysiologic phenotype. Giudicessi et al. (2012) stated that this patient's death during sleep was consistent with a Brugada syndrome-like gain of function as the primary underlying etiology, with a Brugada syndrome-triggered fatal arrhythmia as the chief arrhythmia phenotype. </p>
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<h4>
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<span class="mim-font">
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<strong>.0008 SPINOCEREBELLAR ATAXIA 19</strong>
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</span>
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</h4>
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KCND3, 9-BP DUP, NT877
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ClinVar: RCV003389358, RCV004765816
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<span class="mim-text-font">
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<p>In a 10-year-old boy with spinocerebellar ataxia-19 (SCA19; 607346), Smets et al. (2015) identified a de novo heterozygous 9-bp duplication (c.877_885dupCGCGTCTTC, NM_004980.4) in the KCND3 gene, resulting in a 3-amino acid duplication (Arg293_Phe295dup) of the RVF (Arg-Val-Phe) domain in the S4 segment of Kv4.3. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. Studies to assess the effects of the duplication showed that the mutant protein was properly localized in the cell, but that it had significantly decreased stability. The mutation caused a strong shift in the voltage-dependence of activation and inactivation. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 SPINOCEREBELLAR ATAXIA 19</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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KCND3, GLY384SER
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<br />
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SNP: rs1664632655,
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ClinVar: RCV001289013, RCV003389334, RCV004629532
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<span class="mim-text-font">
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<p>In a 30-year-old Japanese man with spinocerebellar ataxia-19 (SCA19; 607346), Kurihara et al. (2018) identified a de novo heterozygous c.1150G-A transition in the KCND3 gene, resulting in a gly384-to-ser (G384S) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or an in-house dataset of 800 healthy persons. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Chung, M., Lu, Y.-C., Cheng, N.-C., Soong, B.-W.
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<strong>A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23.</strong>
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Brain 126: 1293-1299, 2003.
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[Full Text: https://doi.org/10.1093/brain/awg130]
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</li>
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<p class="mim-text-font">
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Dilks, D., Ling, H.-P., Cockett, M., Sokol, P., Numann, R.
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<strong>Cloning and expression of the human Kv4.3 potassium channel.</strong>
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J. Neurophysiol. 81: 1974-1977, 1999.
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[PubMed: 10200233]
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[Full Text: https://doi.org/10.1152/jn.1999.81.4.1974]
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<p class="mim-text-font">
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Dixon, J. E., Shi, W., Wang, H.-S., McDonald, C., Yu, H., Wymore, R. S., Cohen, I. S., McKinnon, D.
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<strong>Role of the Kv4.3 K+ channel in ventricular muscle: a molecular correlate for the transient outward current.</strong>
|
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Circ. Res. 79: 659-668, 1996. Note: Erratum: Circ. Res. 80: 147 only, 1997.
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[Full Text: https://doi.org/10.1161/01.res.79.4.659]
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<p class="mim-text-font">
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Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Kusters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E., Verbeek, D. S.
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|
<strong>Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19.</strong>
|
|
Ann. Neurol. 72: 870-880, 2012.
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[PubMed: 23280838]
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[Full Text: https://doi.org/10.1002/ana.23700]
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</p>
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<li>
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<p class="mim-text-font">
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Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Ackerman, M. J.
|
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<strong>Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.</strong>
|
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Hum. Mutat. 33: 989-997, 2012.
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[PubMed: 22457051]
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[Full Text: https://doi.org/10.1002/humu.22058]
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</p>
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<li>
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<p class="mim-text-font">
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Giudicessi, J. R., Ye, D., Tester, D. J., Crotti, L., Mugione, A., Nesterenko, V. V., Albertson, R. M., Antzelevitch, C., Schwartz, P. J., Ackerman, M. J.
|
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<strong>Transient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.</strong>
|
|
Heart Rhythm 8: 1024-1032, 2011.
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[PubMed: 21349352]
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[Full Text: https://doi.org/10.1016/j.hrthm.2011.02.021]
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</p>
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<li>
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<p class="mim-text-font">
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Hsiao, C. T., Fu, S. J., Liu, Y. T., Lu, Y. H., Zhong, C. Y., Tang, C. Y., Soong, B. W., Jeng, C. J.
|
|
<strong>Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.</strong>
|
|
Hum. Mutat. 40: 2088-2107, 2019.
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[PubMed: 31293010]
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[Full Text: https://doi.org/10.1002/humu.23865]
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</p>
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<li>
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<p class="mim-text-font">
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Huin, V., Strubi-Vuillaume, I., Dujardin, K., Brion, M., Delliaux, M., Dellacherie, D., Cuvellier, J. C., Cuisset, J. M., Riquet, A., Moreau, C., Defebvre, L., Sablonniere, B., Devos, D.
|
|
<strong>Expanding the phenotype of SCA19/22: parkinsonism, cognitive impairment and epilepsy.</strong>
|
|
Parkinsonism Relat. Disord. 45: 85-89, 2017.
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[PubMed: 28947073]
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[Full Text: https://doi.org/10.1016/j.parkreldis.2017.09.014]
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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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Isbrandt, D., Leicher, T., Waldschutz, R., Zhu, X., Luhmann, U., Michel, U., Sauter, K., Pongs, O.
|
|
<strong>Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(to) and I(sa).</strong>
|
|
Genomics 64: 144-154, 2000.
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[PubMed: 10729221]
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[Full Text: https://doi.org/10.1006/geno.2000.6117]
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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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Kong, W., Po, S., Yamagishi, T., Ashen, M. D., Stetten, G., Tomaselli, G. F.
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<strong>Isolation and characterization of the human gene encoding I(to): further diversity by alternative mRNA splicing.</strong>
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Am. J. Physiol. 275: H1963-H1970, 1998.
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[PubMed: 9843794]
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[Full Text: https://doi.org/10.1152/ajpheart.1998.275.6.H1963]
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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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Kurihara, M., Ishiura, H., Sasaki, T., Otsuka, J., Hayashi, T., Terao, Y., Matsukawa, T., Mitsui, J., Kaneko, J., Nishiyama, K., Doi, K., Yoshimura, J., Morishita, S., Shimizu, J., Tsuji, S.
|
|
<strong>Novel de novo KCND3 mutation in a Japanese patient with intellectual disability, cerebellar ataxia, myoclonus, and dystonia.</strong>
|
|
Cerebellum 17: 237-242, 2018.
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[PubMed: 28895081]
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[Full Text: https://doi.org/10.1007/s12311-017-0883-4]
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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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Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., and 10 others.
|
|
<strong>Mutations in KCND3 cause spinocerebellar ataxia type 22.</strong>
|
|
Ann. Neurol. 72: 859-869, 2012.
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[PubMed: 23280837]
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[Full Text: https://doi.org/10.1002/ana.23701]
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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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Postma, A. V., Bezzina, C. R., de Vries, J. F., Wilde, A. A. M., Moorman, A. F. M., Mannens, M. M. A. M.
|
|
<strong>Genomic organisation and chromosomal localisation of two members of the KCND ion channel family, KCND2 and KCND3.</strong>
|
|
Hum. Genet. 106: 614-619, 2000.
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[PubMed: 10942109]
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[Full Text: https://doi.org/10.1007/s004390000308]
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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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Schelhaas, H. J., Ippel, P. F., Hageman, G., Sinke, R. J., van der Laan, E. N., Beemer, F. A.
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<strong>Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia.</strong>
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J. Neurol. 248: 113-120, 2001.
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[PubMed: 11284128]
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[Full Text: https://doi.org/10.1007/s004150170245]
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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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Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., van de Warrenburg, B. P., Zuchner, S., Gonzalez, M. A., Schule, R., Synofzik, M., Van der Aa, N., De Jonghe, P., Verbeek, D. S., Baets, J.
|
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<strong>First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy.</strong>
|
|
BMC Med. Genet. 16: 51, 2015.
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[PubMed: 26189493]
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[Full Text: https://doi.org/10.1186/s12881-015-0200-3]
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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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Tseng, G.-N.
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<strong>Molecular structure of cardiac I(to) channels: Kv4.2, Kv4.3, and other possibilities?</strong>
|
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Cardiovasc. Res. 41: 16-18, 1999.
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[PubMed: 10325948]
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[Full Text: https://doi.org/10.1016/s0008-6363(98)00282-x]
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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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You, T., Mao, W., Cai, B., Li, F., Xu, H.
|
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<strong>Two novel Brugada syndrome-associated mutations increase Kv4.3 membrane expression and function.</strong>
|
|
Int. J. Molec. Med. 36: 309-315, 2015.
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[PubMed: 26016905]
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[Full Text: https://doi.org/10.3892/ijmm.2015.2223]
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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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Zhu, X. R., Wulf, A., Schwarz, M., Isbrandt, D., Pongs, O.
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<strong>Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current.</strong>
|
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Receptors Channels 6: 387-400, 1999.
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[PubMed: 10551270]
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</p>
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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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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
|
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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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Sonja A. Rasmussen - updated : 11/07/2023<br>Bao Lige - updated : 06/29/2023<br>Marla J. F. O'Neill - updated : 5/29/2015<br>Cassandra L. Kniffin - updated : 10/7/2013<br>Victor A. McKusick - updated : 11/20/2000
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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="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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carol : 11/08/2023<br>carol : 11/07/2023<br>mgross : 06/29/2023<br>carol : 04/12/2017<br>carol : 06/03/2015<br>mcolton : 5/29/2015<br>carol : 10/8/2013<br>carol : 10/8/2013<br>ckniffin : 10/7/2013<br>terry : 11/29/2012<br>carol : 12/23/2002<br>terry : 1/19/2001<br>terry : 1/19/2001<br>carol : 11/20/2000
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