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Entry
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- *600570 - CHLORIDE CHANNEL 2; CLCN2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600570</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="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600570">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000114859;t=ENST00000265593" 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=1181" 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=600570" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000114859;t=ENST00000265593" 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_001171087,NM_001171088,NM_001171089,NM_004366,XM_006713489,XM_011512401,XM_047447419" 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_004366" 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=600570" 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=02782&isoform_id=02782_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/CLCN2" 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/2570864,5724782,18204325,47939636,119598654,119598655,119598656,156104869,194379478,194380406,194386482,283806616,283806618,283806622,288558807,578807031,767925655,957949143,957949147,957949154,957949157,957949160,1031418434,2217341736,2462586975,2462586977,2462586979" 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/P51788" 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=1181" 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=ENSG00000114859;t=ENST00000265593" 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=CLCN2" 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=CLCN2" 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+1181" 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/CLCN2" 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:1181" 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/1181" 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=chr3&hgg_gene=ENST00000265593.9&hgg_start=184346185&hgg_end=184361605&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:2020" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/clcn2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600570[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=600570[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/CLCN2/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/ENSG00000114859" 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=CLCN2" 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=CLCN2" 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=CLCN2" 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=CLCN2&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/PA26547" 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:2020" 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/FBgn0051116.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:105061" 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/CLCN2#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:105061" 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/1181/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=1181" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000528;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000528 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000529;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000529 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000530;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000530 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000531;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000531 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-050506-73" 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:1181" 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=CLCN2&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> 703233008, 768663003<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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600570
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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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CHLORIDE CHANNEL 2; CLCN2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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CLC2
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CLCN2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CLCN2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/3/918?start=-3&limit=10&highlight=918">3q27.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:184346185-184361605&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'})">3:184,346,185-184,361,605</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=607628,607628,607628,605635,615651" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/918?start=-3&limit=10&highlight=918">
|
|
3q27.1
|
|
</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
{Epilepsy, idiopathic generalized, susceptibility to, 11}
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607628"> 607628 </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The CLCN2 gene encodes a voltage-gated chloride channel with high expression in the adrenal glomerulosa. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase (CYP11B2; <a href="/entry/124080">124080</a>) (summary by <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Cid, L. P., Montrose-Rafizadeh, C., Smith, D. I., Guggino, W. B., Cutting, G. R. <strong>Cloning of a putative human voltage-gated chloride channel (CLC-2) cDNA widely expressed in human tissues.</strong> Hum. Molec. Genet. 4: 407-413, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795595</a>] [<a href="https://doi.org/10.1093/hmg/4.3.407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795595">Cid et al. (1995)</a> cloned a human homolog of the rat voltage-gated chloride channel CLC2 from a T84 epithelial cell cDNA library. The predicted 898-amino acid protein is over 93% identical to the rat sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> found expression of the CLCN2 gene predominantly in the zona glomerulosa in the human adrenal cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" 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 mice, <a href="#5" class="mim-tip-reference" title="Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C. <strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong> Nature Genet. 50: 355-361, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403012</a>] [<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403012">Fernandes-Rosa et al. (2018)</a> found expression of the Clcn2 gene in adrenal gland and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR of somatic cell hybrid DNAs, <a href="#3" class="mim-tip-reference" title="Cid, L. P., Montrose-Rafizadeh, C., Smith, D. I., Guggino, W. B., Cutting, G. R. <strong>Cloning of a putative human voltage-gated chloride channel (CLC-2) cDNA widely expressed in human tissues.</strong> Hum. Molec. Genet. 4: 407-413, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795595</a>] [<a href="https://doi.org/10.1093/hmg/4.3.407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795595">Cid et al. (1995)</a> mapped the CLCN2 gene to 3q26-qter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795595" 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="#18" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 09/27/2019."None>Stumpf (2019)</a> mapped the CLCN2 gene to chromosome 3q27.1 based on an alignment of the CLCN2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC072004.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC072004.1</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#14" class="mim-tip-reference" title="Schwiebert, E. M., Cid-Soto, L. P., Stafford, D., Carter, M., Blaisdell, C. J., Zeitlin, P. L., Guggino, W. B., Cutting, G. R. <strong>Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells.</strong> Proc. Nat. Acad. Sci. 95: 3879-3884, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9520461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9520461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9520461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.7.3879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9520461">Schwiebert et al. (1998)</a> found that CLC2 chloride channels are expressed in epithelia affected by cystic fibrosis (CF; <a href="/entry/219700">219700</a>) and raised the possibility that these might represent an alternative target for pharmacotherapy of CF. The explore this possibility, they manipulated genetically the expression levels of CLC2 channels in airway epithelial cells derived from cystic fibrosis patients. Whole-cell patch-clamp analysis of cells overexpressing CLC2 identified hyperpolarization-activated chloride ion currents (HACCs) that displayed time- and voltage-dependent activation and an inwardly rectifying steady-state current voltage relationship. Reduction of extracellular pH to 5.0 caused significant increases in HACCs in overexpressing cells and the appearance of robust currents in parental cells from the cystic fibrosis patient. CF cells stably transfected with the antisense CLC2 cDNA showed reduced expression of CLC2 compared with parental cells by Western blotting, and a significant reduction in the magnitude of pH-dependent HACCs. To determine whether changes in the extracellular pH alone could initiate chloride transport via CLC2 channels, they performed chloride-36 efflux studies on overexpressing cells and cells with endogenous expression of CLC2. Acidic extracellular pH increased chloride-36 efflux rates in both cell types, although the CLC2-overexpressing cells had significantly greater chloride conduction and a longer duration of efflux than the parental cells. Compounds that exploit the pH mechanism of activating endogenous CLC2 channels may provide a pharmacologic option for increasing chloride conductance in airways of CF patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9520461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The chloride homeostasis of neurons and nonneuronal cells is maintained in part by chloride conductance through the CLCN2 channel. By immunostaining, <a href="#15" class="mim-tip-reference" title="Sik, A., Smith, R. L., Freund, T. F. <strong>Distribution of chloride channel-2-immunoreactive neuronal and astrocytic processes in the hippocampus.</strong> Neuroscience 101: 51-65, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11068136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11068136</a>] [<a href="https://doi.org/10.1016/s0306-4522(00)00360-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11068136">Sik et al. (2000)</a> showed that CLCN2 channels were localized in the plasma membranes of dendrites, axons, and somata of pyramidal and nonpyramidal cells of the hippocampus. In addition, the end feet of astrocytes in the neuropil and around small blood vessels were strongly immunoreactive. Localization was within or adjacent to active zones of symmetrical, presumed GABAergic, synapses, and the authors concluded that CLCN2 is involved in transmembrane chloride movements associated with GABAergic synaptic transmission. <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> noted that CLCN2 channels act as a chloride-efflux pathway which establishes and maintains a high transmembrane chloride gradient necessary for an inhibitory GABA response. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11068136+12612585" 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 immunohistochemistry of healthy human brain tissue, <a href="#4" class="mim-tip-reference" title="Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. <strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong> Lancet Neurol. 12: 659-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>] [<a href="https://doi.org/10.1016/S1474-4422(13)70053-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707145">Depienne et al. (2013)</a> found expression of the CLCN2 gene on the surface of cell bodies and processes of virtually all GFAP (<a href="/entry/137780">137780</a>)-positive fibrous astrocytes in the posterior limb of the internal capsule. CLCN2 showed a fine punctate quality, consistent with a membrane protein. CLCN2 was enriched in perivascular astrocytes with GlialCAM (<a href="/entry/611642">611642</a>) and MLC1 (<a href="/entry/605908">605908</a>). CLCN2 expression was also seen along axons, in oligodendrocytes, and in the ependymal lining. CLCN2 was not detected in neuronal perikarya. Electron microscopy confirmed that CLCN2 was present in white matter astrocytes and enriched in cell processes with astrocyte-astrocyte and astrocyte-abaxonal myelin contacts. Immunoreactivity was also visible in astrocytic endfeet around blood vessels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Controversial Role of CLCN2 Mutations in Epilepsy</em></strong></p><p>
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In a genomewide linkage study of 130 families with idiopathic generalized epilepsy (see IGE; <a href="/entry/600669">600669</a>), <a href="#12" class="mim-tip-reference" title="Sander, T., Schulz, H., Saar, K., Gennaro, E., Riggio, M. C., Bianchi, A., Zara, F., Luna, D., Bulteau, C., Kaminska, A., Ville, D., Cieuta, C., and 14 others. <strong>Genome search for susceptibility loci of common idiopathic generalised epilepsies.</strong> Hum. Molec. Genet. 9: 1465-1472, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888596</a>] [<a href="https://doi.org/10.1093/hmg/9.10.1465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888596">Sander et al. (2000)</a> identified a susceptibility locus on chromosome 3q26.1 (EIG11; <a href="/entry/607628">607628</a>). In 3 of 46 unrelated families with IGE localized to 3q26 (including some of the families reported by <a href="#12" class="mim-tip-reference" title="Sander, T., Schulz, H., Saar, K., Gennaro, E., Riggio, M. C., Bianchi, A., Zara, F., Luna, D., Bulteau, C., Kaminska, A., Ville, D., Cieuta, C., and 14 others. <strong>Genome search for susceptibility loci of common idiopathic generalised epilepsies.</strong> Hum. Molec. Genet. 9: 1465-1472, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888596</a>] [<a href="https://doi.org/10.1093/hmg/9.10.1465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888596">Sander et al. (2000)</a>), <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> identified 3 mutations in the CLCN2 gene (<a href="#0001">600570.0001</a>-<a href="#0003">600570.0003</a>). In a reevaluation of 2 of the families reported by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a>, <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a> found discrepancies in the family structure, phenotype, and genetic analysis. On this basis, all but one of the original authors retracted the paper. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12612585+19710712+10888596" 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="#16" class="mim-tip-reference" title="Stogmann, E., Lichtner, P., Baumgartner, C., Schmied, M., Hotzy, C., Asmus, F., Leutmezer, F., Bonelli, S., Assem-Hilger, E., Vass, K., Hatala, K., Strom, T. M., Meitinger, T., Zimprich, F., Zimprich, A. <strong>Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.</strong> Neurogenetics 7: 265-268, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932951</a>] [<a href="https://doi.org/10.1007/s10048-006-0057-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932951">Stogmann et al. (2006)</a> did not identify pathogenic mutations in the CLCN2 gene in 61 patients with IGE or 35 patients with temporal lobe epilepsy, suggesting that CLCN2 gene mutations are not a common cause of these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932951" 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 sequencing of a large collection of human DNA followed by electrophysiologic analysis, <a href="#1" class="mim-tip-reference" title="Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J. <strong>Leukoencephalopathy upon disruption of the chloride channel Clc-2.</strong> J. Neurosci. 27: 6581-6589, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17567819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17567819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17567819[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/10.1523/JNEUROSCI.0338-07.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17567819">Blanz et al. (2007)</a> concluded that several CLCN2 sequence abnormalities previously found in patients with epilepsy most likely represented innocuous polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17567819" 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="#11" class="mim-tip-reference" title="Saint-Martin, C., Gauvain, G., Teodorescu, G., Gourfinkel-An, I., Fedirko, E., Weber, Y. G., Maljevic, S., Ernst, J.-P., Garcia-Olivares, J., Fahlke, C., Nabbout, R., LeGuern, E., Lerche, H., Poncer, J. C., Depienne, C. <strong>Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.</strong> Hum. Mutat. 30: 397-405, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19191339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19191339</a>] [<a href="https://doi.org/10.1002/humu.20876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19191339">Saint-Martin et al. (2009)</a> identified 2 different heterozygous mutations in the CLCN2 gene (<a href="#0004">600570.0004</a>; <a href="#0005">600570.0005</a>) in affected members of 2 unrelated families with juvenile myoclonic epilepsy (EJM8) and idiopathic generalized epilepsy (EIG11), respectively (see <a href="/entry/607628">607628</a>). In both families, the unaffected father also had the mutation, suggesting either reduced penetrance or additional unidentified factors necessary for full phenotypic expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19191339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Niemeyer, M. I., Cid, L. P., Sepulveda, F. V., Blanz, J., Auberson, M., Jentsch, T. J. <strong>No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 42: 3 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037607</a>] [<a href="https://doi.org/10.1038/ng0110-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037607">Niemeyer et al. (2010)</a> disagreed with the conclusion by <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a> that some of the work by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> had merit. Based on lack of functional consequences of the variants reported by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> (<a href="#0001">600570.0001</a>-<a href="#0003">600570.0003</a>), <a href="#9" class="mim-tip-reference" title="Niemeyer, M. I., Cid, L. P., Sepulveda, F. V., Blanz, J., Auberson, M., Jentsch, T. J. <strong>No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 42: 3 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037607</a>] [<a href="https://doi.org/10.1038/ng0110-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037607">Niemeyer et al. (2010)</a> asserted that there is no evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12612585+19710712+20037607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Heyne, H. O., Artomov, M., Battke, F., Bianchini, C., Smith, D. R., Liebmann, N., Tadigotla, V., Stanley, C. M., Lal, D., Rehm, H., Lerche, H., Daly, M. J., Helbig, I., Biskup, S., Weber, Y. G., Lemke, J. R. <strong>Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy.</strong> Genet. Med. 21: 2496-2503, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31056551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31056551</a>] [<a href="https://doi.org/10.1038/s41436-019-0531-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31056551">Heyne et al. (2019)</a> found identical frequencies of ultrarare CLCN2 variants in 6,994 individuals with neurodevelopmental disorder with epilepsy compared with controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31056551" 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>Leukoencephalopathy with Ataxia</em></strong></p><p>
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In 6 unrelated patients with leukoencephalopathy with ataxia (LKPAT; <a href="/entry/615651">615651</a>), <a href="#4" class="mim-tip-reference" title="Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. <strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong> Lancet Neurol. 12: 659-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>] [<a href="https://doi.org/10.1016/S1474-4422(13)70053-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707145">Depienne et al. (2013)</a> identified homozygous or compound heterozygous mutations in the CLCN2 gene (see, e.g., <a href="#0006">600570.0006</a>-<a href="#0009">600570.0009</a>). The initial mutations were found using a combination of homozygosity mapping and whole-exome sequencing, and all mutations were shown to cause a loss of function. Affected individuals had prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggested myelin microvacuolation restricted to certain brain regions. Clinical features included ataxia and unstable gait; some patients had additional features of visual field defects, headaches, and learning disabilities. None of the patients had seizures. The clinical findings were similar to those observed in Clcn2-deficient mice (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Hyperaldosteronism Type 2</em></strong></p><p>
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In affected members of 8 unrelated families with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified 5 different heterozygous missense mutations in the CLCN2 gene (<a href="#0010">600570.0010</a>-<a href="#0014">600570.0014</a>). The mutation in the first family (family 3, originally reported by <a href="#17" class="mim-tip-reference" title="Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L. <strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong> Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>] [<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1521363">Stowasser et al., 1992</a>) was found by exome sequencing and confirmed by Sanger sequencing. The variant segregated with the disorder in the family, although there was evidence of incomplete penetrance and variable disease expressivity. Subsequent CLCN2 mutations in the other families were found by screening the CLCN2 gene in 80 patients with a similar phenotype. In 2 patients, the CLCN2 mutation occurred de novo. One mutation (R172Q; <a href="#0010">600570.0010</a>) was found in 4 unrelated families, and haplotype analysis suggested independent occurrence of the mutation. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that all mutants shifted the activation curve of the channel to more positive voltages with higher open probabilities at the glomerulosa resting potential. All except 1 variant (S865R; <a href="#0012">600570.0012</a>) modified the common gate by increasing the minimum open probability and accelerating activation, resulting in significantly larger chloride efflux compared to wildtype. The S865R variant, which likely has a regulatory function, slowed down deactivation of the gates, with a similar overall effect of increasing chloride flux. The mutations increased expression of CYP11B2 (<a href="/entry/124080">124080</a>) and its upstream regulator NR4A2 (<a href="/entry/601828">601828</a>), which increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings demonstrated a role of anion channels in glomerulosa membrane potential determination and aldosterone production, and further showed that CLCN2 mutations can increase excitatory anion efflux by modifying the voltage dependence of channel opening, resulting in a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29403011+1521363" 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 girl with HALD2, <a href="#5" class="mim-tip-reference" title="Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C. <strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong> Nature Genet. 50: 355-361, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403012</a>] [<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403012">Fernandes-Rosa et al. (2018)</a> identified a de novo heterozygous missense mutation in the CLCN2 gene (G24D; <a href="#0015">600570.0015</a>). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was 1 of 12 patients with early-onset hypertension and hyperaldosteronism who underwent whole-exome sequencing. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of CLCN2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2; <a href="/entry/124080">124080</a>) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. Knockdown of CLCN2 in human adrenocortical cells using shRNA abolished chloride currents and decreased aldosterone production. Sequencing of exon 2 of the CLCN2 gene in 100 patients with bilateral adrenal hyperplasia identified 2 rare heterozygous variants (R66Q and P48R) in 2 patients diagnosed with hypertension at 29 and 19 years, respectively, during pregnancy. However, both variants failed to significantly change CLCN2 currents in Xenopus oocytes. The findings suggested that gain-of-function CLCN2 mutations increase chloride conductance in zona glomerulosa cells, resulting in depolarization and a subsequent increase in opening of voltage-gated calcium channels that trigger autonomous aldosterone production by increasing intracellular calcium concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Bosl, M. R., Stein, V., Hubner, C., Zdebik, A. A., Jordt, S.-E., Mukhopadhyay, A. K., Davidoff, M. S., Holstein, A.-F., Jentsch, T. J. <strong>Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption.</strong> EMBO J. 20: 1289-1299, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11250895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11250895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11250895[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/10.1093/emboj/20.6.1289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11250895">Bosl et al. (2001)</a> found that Clcn2-null mice developed severe degeneration of the retina and the testes, which led to selective male infertility. Seminiferous tubules did not develop lumina, and germ cells failed to complete meiosis. Beginning around puberty there was a massive death of primary spermatocytes and later also of spermatogonia. Tubules were filled with abnormal Sertoli cells, which normally express Clcn2 in patches adjacent to germ cells. In the retina, photoreceptors lacked normal outer segments and degenerated between days P10 and P30. The current across the retinal pigment epithelium was severely reduced at P36. Thus, Clcn2 disruption resulted in the death of 2 cell types that depend on supporting cells that form the blood-testes and blood-retina barriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11250895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J. <strong>Leukoencephalopathy upon disruption of the chloride channel Clc-2.</strong> J. Neurosci. 27: 6581-6589, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17567819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17567819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17567819[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/10.1523/JNEUROSCI.0338-07.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17567819">Blanz et al. (2007)</a> found that Clcn2-null mice were blind and developed progressive widespread spongiform vacuolation of white matter in the brain and spinal cord. Fluid-filled spaces appeared between myelin sheaths of the central but not the peripheral nervous system. However, neuronal morphology appeared normal, and neurologic deficits were mild, mainly including decreased conduction velocity in neurons of the central auditory pathway. The phenotype resembled a leukodystrophy; however, no CLCN2 mutations were found in 150 human leukodystrophy patients. Heterozygous loss of Clcn2 had no detectable functional or morphologic consequences. Neither heterozygous nor homozygous Clcn2 knockout mice had lowered seizure thresholds. <a href="#1" class="mim-tip-reference" title="Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J. <strong>Leukoencephalopathy upon disruption of the chloride channel Clc-2.</strong> J. Neurosci. 27: 6581-6589, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17567819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17567819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17567819[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/10.1523/JNEUROSCI.0338-07.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17567819">Blanz et al. (2007)</a> postulated a role for CLCN2 in glial function and ionic homeostasis in the central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17567819" 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">rs515726131 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726131;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=rs515726131" 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=rs515726131" 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, formerly titled SUSCEPTIBILITY TO JUVENILE MYOCLONIC EPILEPSY 8 based on the report by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a>, has been reclassified based on the findings of <a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> and <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15252188+12612585+19710712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> identified a heterozygous 1-bp insertion (597insG) in the CLCN2 gene in a family in which 4 members had juvenile myoclonic epilepsy (EJM8; see <a href="/entry/607628">607628</a>) and 1 member had epilepsy with grand mal seizures on awakening (EMGA). The insertion mutation resulted in a premature stop codon and a truncated protein lacking major sequence determinants of the ionic pore. Functional studies showed that mutant channels did not yield detectable chloride currents, and the authors suggested that resultant intracellular chloride accumulation would reduce an inhibitory GABA response, resulting in neuronal hyperexcitability and epileptic seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612585" 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 reevaluation of the family reported by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a>, <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a> found that only the proband had JME; no other family members had seizures. In addition, the pedigree structure was different from that previously described, and resequencing of the CLCN2 gene in new blood samples showed that 3 of the original DNA samples were contaminated. On this basis, all but one of the original authors offered a retraction of the paper. However, <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a> noted that the mutation was not observed in 4,700 German control individuals and may act as a susceptibility factor in the development of epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12612585+19710712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The 597insG mutation results in a truncated CLCN2 protein lacking 13 of 18 membrane helices including most putative pore-forming regions, resulting in a loss of function. <a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> showed that coexpression of wildtype and 597insG CLCN2 produced currents with voltage dependence similar to wildtype, but with nonsignificant lower maximal conductance. The authors also showed that the mutant protein did not reach the plasma membrane. The results were not consistent with a dominant-negative effect, and the authors questioned the findings of <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> and the role of CLCN2 mutations in epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15252188+12612585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J. <strong>Leukoencephalopathy upon disruption of the chloride channel Clc-2.</strong> J. Neurosci. 27: 6581-6589, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17567819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17567819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17567819[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/10.1523/JNEUROSCI.0338-07.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17567819">Blanz et al. (2007)</a> found that the 597insG mutant protein lacked dominant-negative effects when coexpressed in Xenopus cells with wildtype CLCN2, suggesting that it has no influence of channel function in the heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17567819" 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">rs515726132 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726132;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=rs515726132" 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=rs515726132" 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, formerly titled EPILEPSY WITH GRAND MAL SEIZURES ON AWAKENING and CHILDHOOD ABSENCE EPILEPSY based on the report by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a>, has been reclassified based on the findings of <a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> and <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15252188+12612585+19710712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> identified a heterozygous 11-bp deletion in intron 2 of the CLCN2 gene close to the splice acceptor site in a family in which several members had epilepsy with grand mal seizures on awakening (EGMA) and 1 member had childhood absence epilepsy (CAE). Of note, the patients who reportedly had EGMA became seizure-free without medication. The mutation resulted in an in-frame deletion of 44 amino acids, predicting the deletion of helix B of the protein. Studies showed that the mutation rendered a nonfunctional chloride channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612585" 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 vitro studies by <a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> showed that coexpression of wildtype and IVS2del11 CLCN2 did not change the characteristics of the wildtype channel. There was also no difference in the proportion of exon-skipped to normally spliced mRNA, predicting no alteration in channel expression in individuals with this variant. The authors also showed that the mutant protein did not reach the plasma membrane. The results were not consistent with a dominant-negative effect, and the authors questioned the findings of <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> and the role of CLCN2 mutations in epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15252188+12612585" 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 reevaluation of the family reported by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a>, <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a> found that only the index case was affected with idiopathic generalized epilepsy (<a href="/entry/607628">607628</a>). This patient's deceased great-grandfather was reportedly affected with epilepsy. Molecular fingerprinting of the original DNA samples showed a discrepancy in the number of individuals from whom a sample was obtained, rendering the results inconclusive. On this basis, all but one of the original authors retracted the paper (<a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al., 2003</a>). <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a> noted, however, that the mutation was not observed in 4,700 German control individuals and may act as a susceptibility factor in the development of epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12612585+19710712" 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> rs137852681 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852681;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/rs137852681?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=rs137852681" 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=rs137852681" 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, formerly titled SUSCEPTIBILITY TO JUVENILE ABSENCE EPILEPSY 2 based on the report by <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a>, has been reclassified based on the findings of <a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> and <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15252188+12612585+19710712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with juvenile absence epilepsy (EJA2; see <a href="/entry/607628">607628</a>), <a href="#6" class="mim-tip-reference" title="Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. <strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong> Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612585</a>] [<a href="https://doi.org/10.1038/ng1121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612585">Haug et al. (2003)</a> identified a heterozygous 2144G-A mutation, resulting in a gly715-to-glu (G715E) substitution. Another sib with generalized spike-wave discharges on EEG also carried the mutation. The father, who also carried the mutation, reportedly had unclassified seizures in childhood, but his severe alcoholism as an adult rendered his disease status uncertain. Functional studies of the mutant channel showed normal current amplitudes, but altered voltage-dependent gating, potentially leading to hyperexcitability. The family structure, diagnosis, and mutation status were confirmed by <a href="#8" class="mim-tip-reference" title="Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. <strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong> Nature Genet. 41: 954-955, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710712</a>] [<a href="https://doi.org/10.1038/ng0909-954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710712">Kleefuss-Lie et al. (2009)</a>. The mutation was not observed in 4,700 German control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12612585+19710712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> stated that the G715E substitution occurs in the long intracellular C terminus of the channel between the 2 CBS domains. In vitro functional studies showed no differences regarding voltage dependence of gating and kinetic parameters between wildtype and G715E channels. The G715E mutant had diminished opening and closing response to ATP, but the effect was not significant when coexpressed with wildtype CLCN2. Although <a href="#10" class="mim-tip-reference" title="Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P. <strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong> Physiol. Genomics 19: 74-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>] [<a href="https://doi.org/10.1152/physiolgenomics.00070.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15252188">Niemeyer et al. (2004)</a> suggested that the effect may become pathologic in conditions of cellular ATP depletion, the observed effect was 'far from being deleterious,' raising doubt about its pathogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15252188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 EPILEPSY, JUVENILE MYOCLONIC, SUSCEPTIBILITY TO, 8</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs71318369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs71318369;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/rs71318369?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=rs71318369" 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=rs71318369" 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=RCV000009605 OR RCV000201836 OR RCV000490413 OR RCV000514822 OR RCV000765717" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009605, RCV000201836, RCV000490413, RCV000514822, RCV000765717" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009605...</a>
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<p>In 2 sibs of Tunisian origin with juvenile myoclonic epilepsy (see <a href="/entry/607628">607628</a>), <a href="#11" class="mim-tip-reference" title="Saint-Martin, C., Gauvain, G., Teodorescu, G., Gourfinkel-An, I., Fedirko, E., Weber, Y. G., Maljevic, S., Ernst, J.-P., Garcia-Olivares, J., Fahlke, C., Nabbout, R., LeGuern, E., Lerche, H., Poncer, J. C., Depienne, C. <strong>Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.</strong> Hum. Mutat. 30: 397-405, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19191339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19191339</a>] [<a href="https://doi.org/10.1002/humu.20876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19191339">Saint-Martin et al. (2009)</a> identified a heterozygous 704G-A transition in the CLCN2 gene, resulting in an arg235-to-gln (R235Q) substitution in a short loop between the fourth and fifth putative transmembrane domains. In vitro functional expression studies showed that the mutant channel had accelerated deactivation rates compared to wildtype, but normal activation and peak current. The mutation was not observed in 263 control individuals from North Africa or 183 French controls. The unaffected father also had the mutation, suggesting either reduced penetrance or that additional unidentified factors are necessary for full phenotypic expression. Another sib with JME was not available for genetic analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19191339" 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> rs137852682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852682;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/rs137852682?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=rs137852682" 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=rs137852682" 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=RCV000009606 OR RCV000201800 OR RCV001348159 OR RCV001794440 OR RCV003987315 OR RCV004549353" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009606, RCV000201800, RCV001348159, RCV001794440, RCV003987315, RCV004549353" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009606...</a>
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<p>In 2 German sibs with idiopathic generalized epilepsy (EIG11; <a href="/entry/607628">607628</a>), <a href="#11" class="mim-tip-reference" title="Saint-Martin, C., Gauvain, G., Teodorescu, G., Gourfinkel-An, I., Fedirko, E., Weber, Y. G., Maljevic, S., Ernst, J.-P., Garcia-Olivares, J., Fahlke, C., Nabbout, R., LeGuern, E., Lerche, H., Poncer, J. C., Depienne, C. <strong>Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.</strong> Hum. Mutat. 30: 397-405, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19191339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19191339</a>] [<a href="https://doi.org/10.1002/humu.20876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19191339">Saint-Martin et al. (2009)</a> identified a heterozygous 1730G-A transition in the CLCN2 gene, resulting in an arg577-to-gln (R577Q) substitution close to the first CBS domain. In vitro functional expression studies showed that the mutant channel had accelerated deactivation rates compared to wildtype, but normal activation and peak current. The mutation was not observed in 203 German controls or 183 French controls. The unaffected father also had the mutation, suggesting either reduced penetrance or that additional unidentified factors are necessary for full phenotypic expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19191339" 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> rs201330912 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201330912;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/rs201330912?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=rs201330912" 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=rs201330912" 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=RCV000087029 OR RCV000599144 OR RCV002490754 OR RCV003326348 OR RCV004689607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087029, RCV000599144, RCV002490754, RCV003326348, RCV004689607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087029...</a>
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<p>In 2 unrelated patients from North Africa with adult-onset leukoencephalopathy with ataxia (LKPAT; <a href="/entry/615651">615651</a>) <a href="#4" class="mim-tip-reference" title="Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. <strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong> Lancet Neurol. 12: 659-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>] [<a href="https://doi.org/10.1016/S1474-4422(13)70053-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707145">Depienne et al. (2013)</a> identified a homozygous c.1709G-A transition in exon 15 of the CLCN2 gene, resulting in a trp570-to-ter (W570X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the HapMap Project or 1000 Genomes Project databases or in controls. Patient fibroblasts showed decreased mutant mRNA, consistent with nonsense-mediated mRNA decay and suggesting a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" 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">rs587777110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777110;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=rs587777110" 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=rs587777110" 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=RCV000087030" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087030" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087030</a>
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<p>In a woman from North Africa, born of consanguineous parents, with adult-onset leukoencephalopathy with ataxia (LKPAT; <a href="/entry/615651">615651</a>), <a href="#4" class="mim-tip-reference" title="Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. <strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong> Lancet Neurol. 12: 659-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>] [<a href="https://doi.org/10.1016/S1474-4422(13)70053-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707145">Depienne et al. (2013)</a> identified a homozygous 6-bp in-frame deletion (c.430_435del) in exon 4 of the CLCN2 gene, resulting in the deletion of 2 highly conserved hydrophobic residues, Leu144 and Ile145, in a transmembrane domain. The mutation, which was found using a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and was not present in the HapMap Project or 1000 Genomes Project databases or in healthy controls. In vitro functional expression assays in COS-7 cells showed that the mutant protein was restricted to the endoplasmic reticulum and hardly reached the plasma membrane. There were also lower amounts of the mutant protein compared to wildtype. These findings were consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" 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> rs587777111 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777111;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/rs587777111?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=rs587777111" 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=rs587777111" 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=RCV000087031" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087031" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087031</a>
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<p>In a boy with childhood-onset leukoencephalopathy with ataxia (LKPAT; <a href="/entry/615651">615651</a>), <a href="#4" class="mim-tip-reference" title="Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. <strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong> Lancet Neurol. 12: 659-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>] [<a href="https://doi.org/10.1016/S1474-4422(13)70053-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707145">Depienne et al. (2013)</a> identified a homozygous c.1499C-T transition in exon 14 of the CLCN2 gene, resulting in an ala500-to-val (A500V) substitution at a highly conserved hydrophobic residue in a transmembrane domain. The unaffected parents were heterozygous for the mutation, which was not found in the HapMap Project or 1000 Genomes Project databases or in healthy controls. In vitro functional expression assays in COS-7 cells showed that the mutant protein was restricted to the endoplasmic reticulum and hardly reached the plasma membrane. There were also lower amounts of the mutant protein compared to wildtype. These findings were consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" 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">rs587777112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777112;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=rs587777112" 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=rs587777112" 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=RCV000087032 OR RCV005089567" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087032, RCV005089567" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087032...</a>
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<p>In a girl, born of consanguineous parents, with childhood-onset leukoencephalopathy with ataxia (LKPAT; <a href="/entry/615651">615651</a>), <a href="#4" class="mim-tip-reference" title="Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. <strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong> Lancet Neurol. 12: 659-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>] [<a href="https://doi.org/10.1016/S1474-4422(13)70053-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707145">Depienne et al. (2013)</a> identified a homozygous 1-bp duplication (c.828dupG) in exon 8 of the CLCN2 gene, resulting in a frameshift and premature termination (Arg277AlafsTer23). The unaffected parents were heterozygous for the mutation, which was not found in the HapMap Project or 1000 Genomes Project databases or in healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" 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> rs1293789661 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1293789661;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/rs1293789661?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=rs1293789661" 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=rs1293789661" 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=RCV000516109 OR RCV002481647" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000516109, RCV002481647" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000516109...</a>
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<p>In affected members of 4 unrelated families (families 3, 1786, 318, and 537) with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified a heterozygous mutation (chr3.184,075,850C-T, GRCh37) in the CLCN2 gene, resulting in a arg172-to-gln (R172Q) substitution at a highly conserved residue. The mutation in family 3 was found by exome sequencing and confirmed by Sanger sequencing; mutations in subsequent families were found by analysis of CLCN2 in exome data or by direct sequencing of CLCN2 in additional patients with a similar phenotype. The mutation segregated with the phenotype in 2 of the families; it occurred de novo in family 318 and was found in only 1 patient in family 537. The mutation was not found in the ExAC or gnomAD databases. Family 3 was originally reported by <a href="#17" class="mim-tip-reference" title="Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L. <strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong> Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>] [<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1521363">Stowasser et al. (1992)</a>. Haplotype analysis suggested independent occurrence of the mutation in the families. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that the R172Q mutation shifted the activation curve of the channel to more positive voltages, which increased the minimum open probability and accelerated activation, resulting in significantly larger chloride efflux compared to wildtype. There was increased expression of CYP11B2 (<a href="/entry/124080">124080</a>) and its upstream regulator NR4A2 (<a href="/entry/601828">601828</a>), which also increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings were consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29403011+1521363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs758379595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs758379595;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/rs758379595?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=rs758379595" 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=rs758379595" 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=RCV000515911" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515911" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515911</a>
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<p>In a 1-year-old girl (family 1281) with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified a de novo heterozygous mutation (chr3.184,076,918, GRCh37) in the CLCN2 gene, resulting in a met22-to-lys (M22K) substitution at a conserved residue. The mutation was not found in the ExAC or gnomAD databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553853557 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553853557;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=rs1553853557" 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=rs1553853557" 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=RCV000515901" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515901" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515901</a>
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<p>In a 20-year-old man (family 840) with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified a heterozygous mutation (chr3.184,064,498T-G, GRCh37) in the CLCN2 gene, resulting in a ser865-to-arg (S865R) substitution at a moderately conserved residue. Parental DNA was not available for segregation analysis, but the parents were reportedly unaffected. The mutation was not found in the ExAC or gnomAD databases. The S865 residue is phosphorylated, suggesting a regulatory function. In vitro cellular functional expression studies showed that the S865R mutation slowed down deactivation of the channel pore gate, resulting in increased pore open probability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553857113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553857113;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=rs1553857113" 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=rs1553857113" 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=RCV000516045" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000516045" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000516045</a>
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<p>In a 20-year-old woman (family 531) with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified a heterozygous mutation (chr3.184,076,907A-T, GRCh37) in the CLCN2 gene, resulting in a tyr26-to-asn (Y26N) substitution at a highly conserved residue. The patient presented with hypertension at age 6 years. Her deceased mother was affected, but DNA was not available for segregation analysis. The mutation was not found in the ExAC or gnomAD databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" 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>.0014 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000677210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000677210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000677210</a>
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<p>In a male infant (family 1492) with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#13" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified a heterozygous mutation (chr3.184,074,782T-A, GRCh37) in the CLCN2 gene, predicted to create a new splice donor site at the end of exon 10. A splicing assay in HEK cells showed that the mutation resulted in an in-frame deletion of codon 362. The patient's mother was affected, but DNA was not available for segregation studies. The mutation was not found in the ExAC or gnomAD databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" 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>.0015 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
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CLCN2, GLY24ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1085307938 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1085307938;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=rs1085307938" 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=rs1085307938" 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=RCV000489700 OR RCV000584655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000489700, RCV000584655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000489700...</a>
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<p>In a girl with familial hyperaldosteronism type 2 (HALD2; <a href="/entry/605635">605635</a>), <a href="#5" class="mim-tip-reference" title="Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C. <strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong> Nature Genet. 50: 355-361, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403012</a>] [<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403012">Fernandes-Rosa et al. (2018)</a> identified a de novo heterozygous c.71G-A transition (c.71G-A, NM_004366) in the CLCN2 gene, resulting in a gly24-to-asp (G24D) substitution at a highly conserved residue in the N-terminal cytoplasmic inactivation domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in an in-house database. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of Clcn2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2; <a href="/entry/124080">124080</a>) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. The data suggested that a gain-of-function CLCN2 mutation may depolarize the cell, activate the steroidogenic pathway, and increase aldosterone production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Blanz2007" class="mim-anchor"></a>
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Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J.
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<strong>Leukoencephalopathy upon disruption of the chloride channel Clc-2.</strong>
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J. Neurosci. 27: 6581-6589, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17567819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17567819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17567819[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=17567819" 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/10.1523/JNEUROSCI.0338-07.2007" target="_blank">Full Text</a>]
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Bosl, M. R., Stein, V., Hubner, C., Zdebik, A. A., Jordt, S.-E., Mukhopadhyay, A. K., Davidoff, M. S., Holstein, A.-F., Jentsch, T. J.
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<strong>Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption.</strong>
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EMBO J. 20: 1289-1299, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11250895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11250895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11250895[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=11250895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/emboj/20.6.1289" target="_blank">Full Text</a>]
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Cid, L. P., Montrose-Rafizadeh, C., Smith, D. I., Guggino, W. B., Cutting, G. R.
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<strong>Cloning of a putative human voltage-gated chloride channel (CLC-2) cDNA widely expressed in human tissues.</strong>
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Hum. Molec. Genet. 4: 407-413, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795595</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/4.3.407" target="_blank">Full Text</a>]
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Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others.
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<strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong>
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Lancet Neurol. 12: 659-668, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707145</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707145" 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/S1474-4422(13)70053-X" target="_blank">Full Text</a>]
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Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C.
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[<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1121" target="_blank">Full Text</a>]
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Heyne, H. O., Artomov, M., Battke, F., Bianchini, C., Smith, D. R., Liebmann, N., Tadigotla, V., Stanley, C. M., Lal, D., Rehm, H., Lerche, H., Daly, M. J., Helbig, I., Biskup, S., Weber, Y. G., Lemke, J. R.
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[<a href="https://doi.org/10.1038/s41436-019-0531-0" target="_blank">Full Text</a>]
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Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others.
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[<a href="https://doi.org/10.1038/ng0909-954" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0110-3" target="_blank">Full Text</a>]
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<a id="Niemeyer2004" class="mim-anchor"></a>
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<strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong>
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Physiol. Genomics 19: 74-83, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15252188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15252188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15252188" 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/physiolgenomics.00070.2004" target="_blank">Full Text</a>]
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<a id="Saint-Martin2009" class="mim-anchor"></a>
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Saint-Martin, C., Gauvain, G., Teodorescu, G., Gourfinkel-An, I., Fedirko, E., Weber, Y. G., Maljevic, S., Ernst, J.-P., Garcia-Olivares, J., Fahlke, C., Nabbout, R., LeGuern, E., Lerche, H., Poncer, J. C., Depienne, C.
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Hum. Mutat. 30: 397-405, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19191339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19191339</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19191339" 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.20876" target="_blank">Full Text</a>]
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<a id="Sander2000" class="mim-anchor"></a>
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Sander, T., Schulz, H., Saar, K., Gennaro, E., Riggio, M. C., Bianchi, A., Zara, F., Luna, D., Bulteau, C., Kaminska, A., Ville, D., Cieuta, C., and 14 others.
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[<a href="https://doi.org/10.1093/hmg/9.10.1465" target="_blank">Full Text</a>]
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<a id="Scholl2018" class="mim-anchor"></a>
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Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others.
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<strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong>
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Nature Genet. 50: 349-354, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[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=29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank">Full Text</a>]
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<a id="Schwiebert1998" class="mim-anchor"></a>
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Schwiebert, E. M., Cid-Soto, L. P., Stafford, D., Carter, M., Blaisdell, C. J., Zeitlin, P. L., Guggino, W. B., Cutting, G. R.
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<strong>Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9520461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9520461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9520461[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=9520461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.95.7.3879" target="_blank">Full Text</a>]
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<strong>Distribution of chloride channel-2-immunoreactive neuronal and astrocytic processes in the hippocampus.</strong>
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[<a href="https://doi.org/10.1016/s0306-4522(00)00360-2" target="_blank">Full Text</a>]
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Stogmann, E., Lichtner, P., Baumgartner, C., Schmied, M., Hotzy, C., Asmus, F., Leutmezer, F., Bonelli, S., Assem-Hilger, E., Vass, K., Hatala, K., Strom, T. M., Meitinger, T., Zimprich, F., Zimprich, A.
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<strong>Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932951</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932951" 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/s10048-006-0057-x" target="_blank">Full Text</a>]
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Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L.
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[<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank">Full Text</a>]
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 09/27/2019.
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 06/28/2024
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 09/27/2019<br>Cassandra L. Kniffin - updated : 08/09/2018<br>Cassandra L. Kniffin - updated : 2/19/2014<br>Cassandra L. Kniffin - updated : 1/19/2010<br>Cassandra L. Kniffin - updated : 10/2/2009<br>Cassandra L. Kniffin - updated : 12/6/2006<br>Cassandra L. Kniffin - reorganized : 4/9/2003<br>Cassandra L. Kniffin - updated : 3/17/2003<br>Victor A. McKusick - updated : 5/1/1998
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Victor A. McKusick : 6/1/1995
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 06/28/2024
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alopez : 05/06/2021<br>carol : 09/30/2019<br>alopez : 09/27/2019<br>alopez : 07/15/2019<br>carol : 09/11/2018<br>carol : 08/13/2018<br>carol : 08/10/2018<br>ckniffin : 08/09/2018<br>carol : 02/19/2014<br>mcolton : 2/19/2014<br>ckniffin : 2/19/2014<br>terry : 11/3/2010<br>alopez : 2/1/2010<br>ckniffin : 2/1/2010<br>carol : 1/29/2010<br>alopez : 1/28/2010<br>ckniffin : 1/19/2010<br>carol : 12/24/2009<br>terry : 10/21/2009<br>carol : 10/6/2009<br>ckniffin : 10/2/2009<br>wwang : 12/7/2006<br>ckniffin : 12/6/2006<br>carol : 4/9/2003<br>ckniffin : 3/17/2003<br>alopez : 5/15/1998<br>terry : 5/1/1998<br>mark : 6/1/1995
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<span class="mim-font">
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<strong>*</strong> 600570
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<h3>
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CHLORIDE CHANNEL 2; CLCN2
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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CLC2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CLCN2</em></strong>
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<strong>SNOMEDCT:</strong> 703233008, 768663003;
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Cytogenetic location: 3q27.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:184,346,185-184,361,605 </span>
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</em>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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3q27.1
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{Epilepsy, idiopathic generalized, susceptibility to, 11}
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607628
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Autosomal dominant
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3
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{Epilepsy, juvenile absence, susceptibility to, 2}
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<span class="mim-font">
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607628
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Autosomal dominant
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3
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{Epilepsy, juvenile myoclonic, susceptibility to, 8}
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607628
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Autosomal dominant
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3
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Hyperaldosteronism, familial, type II
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605635
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Autosomal dominant
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3
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Leukoencephalopathy with ataxia
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615651
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Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The CLCN2 gene encodes a voltage-gated chloride channel with high expression in the adrenal glomerulosa. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase (CYP11B2; 124080) (summary by Scholl et al., 2018). </p>
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<strong>Cloning and Expression</strong>
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<p>Cid et al. (1995) cloned a human homolog of the rat voltage-gated chloride channel CLC2 from a T84 epithelial cell cDNA library. The predicted 898-amino acid protein is over 93% identical to the rat sequence. </p><p>Scholl et al. (2018) found expression of the CLCN2 gene predominantly in the zona glomerulosa in the human adrenal cortex. </p><p>In mice, Fernandes-Rosa et al. (2018) found expression of the Clcn2 gene in adrenal gland and brain. </p>
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<strong>Mapping</strong>
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<p>By PCR of somatic cell hybrid DNAs, Cid et al. (1995) mapped the CLCN2 gene to 3q26-qter. </p><p>Stumpf (2019) mapped the CLCN2 gene to chromosome 3q27.1 based on an alignment of the CLCN2 sequence (GenBank BC072004.1) with the genomic sequence (GRCh38).</p>
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<strong>Gene Function</strong>
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<p>Schwiebert et al. (1998) found that CLC2 chloride channels are expressed in epithelia affected by cystic fibrosis (CF; 219700) and raised the possibility that these might represent an alternative target for pharmacotherapy of CF. The explore this possibility, they manipulated genetically the expression levels of CLC2 channels in airway epithelial cells derived from cystic fibrosis patients. Whole-cell patch-clamp analysis of cells overexpressing CLC2 identified hyperpolarization-activated chloride ion currents (HACCs) that displayed time- and voltage-dependent activation and an inwardly rectifying steady-state current voltage relationship. Reduction of extracellular pH to 5.0 caused significant increases in HACCs in overexpressing cells and the appearance of robust currents in parental cells from the cystic fibrosis patient. CF cells stably transfected with the antisense CLC2 cDNA showed reduced expression of CLC2 compared with parental cells by Western blotting, and a significant reduction in the magnitude of pH-dependent HACCs. To determine whether changes in the extracellular pH alone could initiate chloride transport via CLC2 channels, they performed chloride-36 efflux studies on overexpressing cells and cells with endogenous expression of CLC2. Acidic extracellular pH increased chloride-36 efflux rates in both cell types, although the CLC2-overexpressing cells had significantly greater chloride conduction and a longer duration of efflux than the parental cells. Compounds that exploit the pH mechanism of activating endogenous CLC2 channels may provide a pharmacologic option for increasing chloride conductance in airways of CF patients. </p><p>The chloride homeostasis of neurons and nonneuronal cells is maintained in part by chloride conductance through the CLCN2 channel. By immunostaining, Sik et al. (2000) showed that CLCN2 channels were localized in the plasma membranes of dendrites, axons, and somata of pyramidal and nonpyramidal cells of the hippocampus. In addition, the end feet of astrocytes in the neuropil and around small blood vessels were strongly immunoreactive. Localization was within or adjacent to active zones of symmetrical, presumed GABAergic, synapses, and the authors concluded that CLCN2 is involved in transmembrane chloride movements associated with GABAergic synaptic transmission. Haug et al. (2003) noted that CLCN2 channels act as a chloride-efflux pathway which establishes and maintains a high transmembrane chloride gradient necessary for an inhibitory GABA response. </p><p>Using immunohistochemistry of healthy human brain tissue, Depienne et al. (2013) found expression of the CLCN2 gene on the surface of cell bodies and processes of virtually all GFAP (137780)-positive fibrous astrocytes in the posterior limb of the internal capsule. CLCN2 showed a fine punctate quality, consistent with a membrane protein. CLCN2 was enriched in perivascular astrocytes with GlialCAM (611642) and MLC1 (605908). CLCN2 expression was also seen along axons, in oligodendrocytes, and in the ependymal lining. CLCN2 was not detected in neuronal perikarya. Electron microscopy confirmed that CLCN2 was present in white matter astrocytes and enriched in cell processes with astrocyte-astrocyte and astrocyte-abaxonal myelin contacts. Immunoreactivity was also visible in astrocytic endfeet around blood vessels. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Controversial Role of CLCN2 Mutations in Epilepsy</em></strong></p><p>
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In a genomewide linkage study of 130 families with idiopathic generalized epilepsy (see IGE; 600669), Sander et al. (2000) identified a susceptibility locus on chromosome 3q26.1 (EIG11; 607628). In 3 of 46 unrelated families with IGE localized to 3q26 (including some of the families reported by Sander et al. (2000)), Haug et al. (2003) identified 3 mutations in the CLCN2 gene (600570.0001-600570.0003). In a reevaluation of 2 of the families reported by Haug et al. (2003), Kleefuss-Lie et al. (2009) found discrepancies in the family structure, phenotype, and genetic analysis. On this basis, all but one of the original authors retracted the paper. </p><p>Stogmann et al. (2006) did not identify pathogenic mutations in the CLCN2 gene in 61 patients with IGE or 35 patients with temporal lobe epilepsy, suggesting that CLCN2 gene mutations are not a common cause of these disorders. </p><p>By sequencing of a large collection of human DNA followed by electrophysiologic analysis, Blanz et al. (2007) concluded that several CLCN2 sequence abnormalities previously found in patients with epilepsy most likely represented innocuous polymorphisms. </p><p>Saint-Martin et al. (2009) identified 2 different heterozygous mutations in the CLCN2 gene (600570.0004; 600570.0005) in affected members of 2 unrelated families with juvenile myoclonic epilepsy (EJM8) and idiopathic generalized epilepsy (EIG11), respectively (see 607628). In both families, the unaffected father also had the mutation, suggesting either reduced penetrance or additional unidentified factors necessary for full phenotypic expression. </p><p>Niemeyer et al. (2010) disagreed with the conclusion by Kleefuss-Lie et al. (2009) that some of the work by Haug et al. (2003) had merit. Based on lack of functional consequences of the variants reported by Haug et al. (2003) (600570.0001-600570.0003), Niemeyer et al. (2010) asserted that there is no evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. </p><p>Heyne et al. (2019) found identical frequencies of ultrarare CLCN2 variants in 6,994 individuals with neurodevelopmental disorder with epilepsy compared with controls. </p><p><strong><em>Leukoencephalopathy with Ataxia</em></strong></p><p>
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In 6 unrelated patients with leukoencephalopathy with ataxia (LKPAT; 615651), Depienne et al. (2013) identified homozygous or compound heterozygous mutations in the CLCN2 gene (see, e.g., 600570.0006-600570.0009). The initial mutations were found using a combination of homozygosity mapping and whole-exome sequencing, and all mutations were shown to cause a loss of function. Affected individuals had prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggested myelin microvacuolation restricted to certain brain regions. Clinical features included ataxia and unstable gait; some patients had additional features of visual field defects, headaches, and learning disabilities. None of the patients had seizures. The clinical findings were similar to those observed in Clcn2-deficient mice (see ANIMAL MODEL). </p><p><strong><em>Familial Hyperaldosteronism Type 2</em></strong></p><p>
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In affected members of 8 unrelated families with familial hyperaldosteronism type 2 (HALD2; 605635), Scholl et al. (2018) identified 5 different heterozygous missense mutations in the CLCN2 gene (600570.0010-600570.0014). The mutation in the first family (family 3, originally reported by Stowasser et al., 1992) was found by exome sequencing and confirmed by Sanger sequencing. The variant segregated with the disorder in the family, although there was evidence of incomplete penetrance and variable disease expressivity. Subsequent CLCN2 mutations in the other families were found by screening the CLCN2 gene in 80 patients with a similar phenotype. In 2 patients, the CLCN2 mutation occurred de novo. One mutation (R172Q; 600570.0010) was found in 4 unrelated families, and haplotype analysis suggested independent occurrence of the mutation. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that all mutants shifted the activation curve of the channel to more positive voltages with higher open probabilities at the glomerulosa resting potential. All except 1 variant (S865R; 600570.0012) modified the common gate by increasing the minimum open probability and accelerating activation, resulting in significantly larger chloride efflux compared to wildtype. The S865R variant, which likely has a regulatory function, slowed down deactivation of the gates, with a similar overall effect of increasing chloride flux. The mutations increased expression of CYP11B2 (124080) and its upstream regulator NR4A2 (601828), which increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings demonstrated a role of anion channels in glomerulosa membrane potential determination and aldosterone production, and further showed that CLCN2 mutations can increase excitatory anion efflux by modifying the voltage dependence of channel opening, resulting in a gain of function. </p><p>In a girl with HALD2, Fernandes-Rosa et al. (2018) identified a de novo heterozygous missense mutation in the CLCN2 gene (G24D; 600570.0015). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was 1 of 12 patients with early-onset hypertension and hyperaldosteronism who underwent whole-exome sequencing. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of CLCN2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2; 124080) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. Knockdown of CLCN2 in human adrenocortical cells using shRNA abolished chloride currents and decreased aldosterone production. Sequencing of exon 2 of the CLCN2 gene in 100 patients with bilateral adrenal hyperplasia identified 2 rare heterozygous variants (R66Q and P48R) in 2 patients diagnosed with hypertension at 29 and 19 years, respectively, during pregnancy. However, both variants failed to significantly change CLCN2 currents in Xenopus oocytes. The findings suggested that gain-of-function CLCN2 mutations increase chloride conductance in zona glomerulosa cells, resulting in depolarization and a subsequent increase in opening of voltage-gated calcium channels that trigger autonomous aldosterone production by increasing intracellular calcium concentrations. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<p>Bosl et al. (2001) found that Clcn2-null mice developed severe degeneration of the retina and the testes, which led to selective male infertility. Seminiferous tubules did not develop lumina, and germ cells failed to complete meiosis. Beginning around puberty there was a massive death of primary spermatocytes and later also of spermatogonia. Tubules were filled with abnormal Sertoli cells, which normally express Clcn2 in patches adjacent to germ cells. In the retina, photoreceptors lacked normal outer segments and degenerated between days P10 and P30. The current across the retinal pigment epithelium was severely reduced at P36. Thus, Clcn2 disruption resulted in the death of 2 cell types that depend on supporting cells that form the blood-testes and blood-retina barriers. </p><p>Blanz et al. (2007) found that Clcn2-null mice were blind and developed progressive widespread spongiform vacuolation of white matter in the brain and spinal cord. Fluid-filled spaces appeared between myelin sheaths of the central but not the peripheral nervous system. However, neuronal morphology appeared normal, and neurologic deficits were mild, mainly including decreased conduction velocity in neurons of the central auditory pathway. The phenotype resembled a leukodystrophy; however, no CLCN2 mutations were found in 150 human leukodystrophy patients. Heterozygous loss of Clcn2 had no detectable functional or morphologic consequences. Neither heterozygous nor homozygous Clcn2 knockout mice had lowered seizure thresholds. Blanz et al. (2007) postulated a role for CLCN2 in glial function and ionic homeostasis in the central nervous system. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<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>15 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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, 1-BP INS, 597G
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<br />
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SNP: rs515726131,
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ClinVar: RCV000009602, RCV000201815
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled SUSCEPTIBILITY TO JUVENILE MYOCLONIC EPILEPSY 8 based on the report by Haug et al. (2003), has been reclassified based on the findings of Niemeyer et al. (2004) and Kleefuss-Lie et al. (2009). </p><p>Haug et al. (2003) identified a heterozygous 1-bp insertion (597insG) in the CLCN2 gene in a family in which 4 members had juvenile myoclonic epilepsy (EJM8; see 607628) and 1 member had epilepsy with grand mal seizures on awakening (EMGA). The insertion mutation resulted in a premature stop codon and a truncated protein lacking major sequence determinants of the ionic pore. Functional studies showed that mutant channels did not yield detectable chloride currents, and the authors suggested that resultant intracellular chloride accumulation would reduce an inhibitory GABA response, resulting in neuronal hyperexcitability and epileptic seizures. </p><p>In a reevaluation of the family reported by Haug et al. (2003), Kleefuss-Lie et al. (2009) found that only the proband had JME; no other family members had seizures. In addition, the pedigree structure was different from that previously described, and resequencing of the CLCN2 gene in new blood samples showed that 3 of the original DNA samples were contaminated. On this basis, all but one of the original authors offered a retraction of the paper. However, Kleefuss-Lie et al. (2009) noted that the mutation was not observed in 4,700 German control individuals and may act as a susceptibility factor in the development of epilepsy. </p><p>The 597insG mutation results in a truncated CLCN2 protein lacking 13 of 18 membrane helices including most putative pore-forming regions, resulting in a loss of function. Niemeyer et al. (2004) showed that coexpression of wildtype and 597insG CLCN2 produced currents with voltage dependence similar to wildtype, but with nonsignificant lower maximal conductance. The authors also showed that the mutant protein did not reach the plasma membrane. The results were not consistent with a dominant-negative effect, and the authors questioned the findings of Haug et al. (2003) and the role of CLCN2 mutations in epilepsy. </p><p>Blanz et al. (2007) found that the 597insG mutant protein lacked dominant-negative effects when coexpressed in Xenopus cells with wildtype CLCN2, suggesting that it has no influence of channel function in the heterozygous state. </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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, IVS2, 11-BP DEL
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<br />
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SNP: rs515726132,
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ClinVar: RCV000009603, RCV000201804, RCV002512946
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled EPILEPSY WITH GRAND MAL SEIZURES ON AWAKENING and CHILDHOOD ABSENCE EPILEPSY based on the report by Haug et al. (2003), has been reclassified based on the findings of Niemeyer et al. (2004) and Kleefuss-Lie et al. (2009). </p><p>Haug et al. (2003) identified a heterozygous 11-bp deletion in intron 2 of the CLCN2 gene close to the splice acceptor site in a family in which several members had epilepsy with grand mal seizures on awakening (EGMA) and 1 member had childhood absence epilepsy (CAE). Of note, the patients who reportedly had EGMA became seizure-free without medication. The mutation resulted in an in-frame deletion of 44 amino acids, predicting the deletion of helix B of the protein. Studies showed that the mutation rendered a nonfunctional chloride channel. </p><p>In vitro studies by Niemeyer et al. (2004) showed that coexpression of wildtype and IVS2del11 CLCN2 did not change the characteristics of the wildtype channel. There was also no difference in the proportion of exon-skipped to normally spliced mRNA, predicting no alteration in channel expression in individuals with this variant. The authors also showed that the mutant protein did not reach the plasma membrane. The results were not consistent with a dominant-negative effect, and the authors questioned the findings of Haug et al. (2003) and the role of CLCN2 mutations in epilepsy. </p><p>In a reevaluation of the family reported by Haug et al. (2003), Kleefuss-Lie et al. (2009) found that only the index case was affected with idiopathic generalized epilepsy (607628). This patient's deceased great-grandfather was reportedly affected with epilepsy. Molecular fingerprinting of the original DNA samples showed a discrepancy in the number of individuals from whom a sample was obtained, rendering the results inconclusive. On this basis, all but one of the original authors retracted the paper (Haug et al., 2003). Kleefuss-Lie et al. (2009) noted, however, that the mutation was not observed in 4,700 German control individuals and may act as a susceptibility factor in the development of 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">
|
|
<strong>.0003 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, GLY715GLU
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<br />
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SNP: rs137852681,
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gnomAD: rs137852681,
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ClinVar: RCV000009604, RCV000201807
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>This variant, formerly titled SUSCEPTIBILITY TO JUVENILE ABSENCE EPILEPSY 2 based on the report by Haug et al. (2003), has been reclassified based on the findings of Niemeyer et al. (2004) and Kleefuss-Lie et al. (2009). </p><p>In 2 sibs with juvenile absence epilepsy (EJA2; see 607628), Haug et al. (2003) identified a heterozygous 2144G-A mutation, resulting in a gly715-to-glu (G715E) substitution. Another sib with generalized spike-wave discharges on EEG also carried the mutation. The father, who also carried the mutation, reportedly had unclassified seizures in childhood, but his severe alcoholism as an adult rendered his disease status uncertain. Functional studies of the mutant channel showed normal current amplitudes, but altered voltage-dependent gating, potentially leading to hyperexcitability. The family structure, diagnosis, and mutation status were confirmed by Kleefuss-Lie et al. (2009). The mutation was not observed in 4,700 German control individuals. </p><p>Niemeyer et al. (2004) stated that the G715E substitution occurs in the long intracellular C terminus of the channel between the 2 CBS domains. In vitro functional studies showed no differences regarding voltage dependence of gating and kinetic parameters between wildtype and G715E channels. The G715E mutant had diminished opening and closing response to ATP, but the effect was not significant when coexpressed with wildtype CLCN2. Although Niemeyer et al. (2004) suggested that the effect may become pathologic in conditions of cellular ATP depletion, the observed effect was 'far from being deleterious,' raising doubt about its pathogenicity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 EPILEPSY, JUVENILE MYOCLONIC, SUSCEPTIBILITY TO, 8</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, ARG235GLN
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<br />
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SNP: rs71318369,
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gnomAD: rs71318369,
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ClinVar: RCV000009605, RCV000201836, RCV000490413, RCV000514822, RCV000765717
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 sibs of Tunisian origin with juvenile myoclonic epilepsy (see 607628), Saint-Martin et al. (2009) identified a heterozygous 704G-A transition in the CLCN2 gene, resulting in an arg235-to-gln (R235Q) substitution in a short loop between the fourth and fifth putative transmembrane domains. In vitro functional expression studies showed that the mutant channel had accelerated deactivation rates compared to wildtype, but normal activation and peak current. The mutation was not observed in 263 control individuals from North Africa or 183 French controls. The unaffected father also had the mutation, suggesting either reduced penetrance or that additional unidentified factors are necessary for full phenotypic expression. Another sib with JME was not available for genetic analysis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 11</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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CLCN2, ARG577GLN
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<br />
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|
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SNP: rs137852682,
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|
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gnomAD: rs137852682,
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|
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ClinVar: RCV000009606, RCV000201800, RCV001348159, RCV001794440, RCV003987315, RCV004549353
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 German sibs with idiopathic generalized epilepsy (EIG11; 607628), Saint-Martin et al. (2009) identified a heterozygous 1730G-A transition in the CLCN2 gene, resulting in an arg577-to-gln (R577Q) substitution close to the first CBS domain. In vitro functional expression studies showed that the mutant channel had accelerated deactivation rates compared to wildtype, but normal activation and peak current. The mutation was not observed in 203 German controls or 183 French controls. The unaffected father also had the mutation, suggesting either reduced penetrance or that additional unidentified factors are necessary for full phenotypic expression. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LEUKOENCEPHALOPATHY WITH ATAXIA</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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CLCN2, TRP570TER
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<br />
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SNP: rs201330912,
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gnomAD: rs201330912,
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ClinVar: RCV000087029, RCV000599144, RCV002490754, RCV003326348, RCV004689607
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients from North Africa with adult-onset leukoencephalopathy with ataxia (LKPAT; 615651) Depienne et al. (2013) identified a homozygous c.1709G-A transition in exon 15 of the CLCN2 gene, resulting in a trp570-to-ter (W570X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the HapMap Project or 1000 Genomes Project databases or in controls. Patient fibroblasts showed decreased mutant mRNA, consistent with nonsense-mediated mRNA decay and suggesting a loss of function. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LEUKOENCEPHALOPATHY WITH ATAXIA</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
CLCN2, 6-BP DEL, NT430
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<br />
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|
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SNP: rs587777110,
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|
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ClinVar: RCV000087030
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman from North Africa, born of consanguineous parents, with adult-onset leukoencephalopathy with ataxia (LKPAT; 615651), Depienne et al. (2013) identified a homozygous 6-bp in-frame deletion (c.430_435del) in exon 4 of the CLCN2 gene, resulting in the deletion of 2 highly conserved hydrophobic residues, Leu144 and Ile145, in a transmembrane domain. The mutation, which was found using a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and was not present in the HapMap Project or 1000 Genomes Project databases or in healthy controls. In vitro functional expression assays in COS-7 cells showed that the mutant protein was restricted to the endoplasmic reticulum and hardly reached the plasma membrane. There were also lower amounts of the mutant protein compared to wildtype. These findings were consistent with a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 LEUKOENCEPHALOPATHY WITH ATAXIA</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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CLCN2, ALA500VAL
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<br />
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SNP: rs587777111,
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gnomAD: rs587777111,
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ClinVar: RCV000087031
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a boy with childhood-onset leukoencephalopathy with ataxia (LKPAT; 615651), Depienne et al. (2013) identified a homozygous c.1499C-T transition in exon 14 of the CLCN2 gene, resulting in an ala500-to-val (A500V) substitution at a highly conserved hydrophobic residue in a transmembrane domain. The unaffected parents were heterozygous for the mutation, which was not found in the HapMap Project or 1000 Genomes Project databases or in healthy controls. In vitro functional expression assays in COS-7 cells showed that the mutant protein was restricted to the endoplasmic reticulum and hardly reached the plasma membrane. There were also lower amounts of the mutant protein compared to wildtype. These findings were consistent with a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LEUKOENCEPHALOPATHY WITH ATAXIA</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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CLCN2, 1-BP DUP, 828G
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<br />
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SNP: rs587777112,
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ClinVar: RCV000087032, RCV005089567
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a girl, born of consanguineous parents, with childhood-onset leukoencephalopathy with ataxia (LKPAT; 615651), Depienne et al. (2013) identified a homozygous 1-bp duplication (c.828dupG) in exon 8 of the CLCN2 gene, resulting in a frameshift and premature termination (Arg277AlafsTer23). The unaffected parents were heterozygous for the mutation, which was not found in the HapMap Project or 1000 Genomes Project databases or in healthy controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0010 HYPERALDOSTERONISM, FAMILIAL, TYPE II</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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CLCN2, ARG172GLN
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<br />
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SNP: rs1293789661,
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gnomAD: rs1293789661,
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ClinVar: RCV000516109, RCV002481647
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of 4 unrelated families (families 3, 1786, 318, and 537) with familial hyperaldosteronism type 2 (HALD2; 605635), Scholl et al. (2018) identified a heterozygous mutation (chr3.184,075,850C-T, GRCh37) in the CLCN2 gene, resulting in a arg172-to-gln (R172Q) substitution at a highly conserved residue. The mutation in family 3 was found by exome sequencing and confirmed by Sanger sequencing; mutations in subsequent families were found by analysis of CLCN2 in exome data or by direct sequencing of CLCN2 in additional patients with a similar phenotype. The mutation segregated with the phenotype in 2 of the families; it occurred de novo in family 318 and was found in only 1 patient in family 537. The mutation was not found in the ExAC or gnomAD databases. Family 3 was originally reported by Stowasser et al. (1992). Haplotype analysis suggested independent occurrence of the mutation in the families. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that the R172Q mutation shifted the activation curve of the channel to more positive voltages, which increased the minimum open probability and accelerated activation, resulting in significantly larger chloride efflux compared to wildtype. There was increased expression of CYP11B2 (124080) and its upstream regulator NR4A2 (601828), which also increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings were consistent with a gain of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0011 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
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</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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CLCN2, MET22LYS
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<br />
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SNP: rs758379595,
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gnomAD: rs758379595,
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|
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ClinVar: RCV000515911
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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 1-year-old girl (family 1281) with familial hyperaldosteronism type 2 (HALD2; 605635), Scholl et al. (2018) identified a de novo heterozygous mutation (chr3.184,076,918, GRCh37) in the CLCN2 gene, resulting in a met22-to-lys (M22K) substitution at a conserved residue. The mutation was not found in the ExAC or gnomAD databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0012 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
|
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</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, SER865ARG
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<br />
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SNP: rs1553853557,
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ClinVar: RCV000515901
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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 20-year-old man (family 840) with familial hyperaldosteronism type 2 (HALD2; 605635), Scholl et al. (2018) identified a heterozygous mutation (chr3.184,064,498T-G, GRCh37) in the CLCN2 gene, resulting in a ser865-to-arg (S865R) substitution at a moderately conserved residue. Parental DNA was not available for segregation analysis, but the parents were reportedly unaffected. The mutation was not found in the ExAC or gnomAD databases. The S865 residue is phosphorylated, suggesting a regulatory function. In vitro cellular functional expression studies showed that the S865R mutation slowed down deactivation of the channel pore gate, resulting in increased pore open probability. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0013 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, TYR26ASN
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<br />
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SNP: rs1553857113,
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ClinVar: RCV000516045
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 20-year-old woman (family 531) with familial hyperaldosteronism type 2 (HALD2; 605635), Scholl et al. (2018) identified a heterozygous mutation (chr3.184,076,907A-T, GRCh37) in the CLCN2 gene, resulting in a tyr26-to-asn (Y26N) substitution at a highly conserved residue. The patient presented with hypertension at age 6 years. Her deceased mother was affected, but DNA was not available for segregation analysis. The mutation was not found in the ExAC or gnomAD databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0014 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, LYS362DEL
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<br />
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ClinVar: RCV000677210
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a male infant (family 1492) with familial hyperaldosteronism type 2 (HALD2; 605635), Scholl et al. (2018) identified a heterozygous mutation (chr3.184,074,782T-A, GRCh37) in the CLCN2 gene, predicted to create a new splice donor site at the end of exon 10. A splicing assay in HEK cells showed that the mutation resulted in an in-frame deletion of codon 362. The patient's mother was affected, but DNA was not available for segregation studies. The mutation was not found in the ExAC or gnomAD databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0015 HYPERALDOSTERONISM, FAMILIAL, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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CLCN2, GLY24ASP
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<br />
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SNP: rs1085307938,
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|
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ClinVar: RCV000489700, RCV000584655
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|
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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 girl with familial hyperaldosteronism type 2 (HALD2; 605635), Fernandes-Rosa et al. (2018) identified a de novo heterozygous c.71G-A transition (c.71G-A, NM_004366) in the CLCN2 gene, resulting in a gly24-to-asp (G24D) substitution at a highly conserved residue in the N-terminal cytoplasmic inactivation domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in an in-house database. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of Clcn2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2; 124080) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. The data suggested that a gain-of-function CLCN2 mutation may depolarize the cell, activate the steroidogenic pathway, and increase aldosterone production. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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<ol>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J.
|
|
<strong>Leukoencephalopathy upon disruption of the chloride channel Clc-2.</strong>
|
|
J. Neurosci. 27: 6581-6589, 2007.
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[PubMed: 17567819]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.0338-07.2007]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Bosl, M. R., Stein, V., Hubner, C., Zdebik, A. A., Jordt, S.-E., Mukhopadhyay, A. K., Davidoff, M. S., Holstein, A.-F., Jentsch, T. J.
|
|
<strong>Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption.</strong>
|
|
EMBO J. 20: 1289-1299, 2001.
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[PubMed: 11250895]
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[Full Text: https://doi.org/10.1093/emboj/20.6.1289]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cid, L. P., Montrose-Rafizadeh, C., Smith, D. I., Guggino, W. B., Cutting, G. R.
|
|
<strong>Cloning of a putative human voltage-gated chloride channel (CLC-2) cDNA widely expressed in human tissues.</strong>
|
|
Hum. Molec. Genet. 4: 407-413, 1995.
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[PubMed: 7795595]
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[Full Text: https://doi.org/10.1093/hmg/4.3.407]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others.
|
|
<strong>Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.</strong>
|
|
Lancet Neurol. 12: 659-668, 2013.
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|
|
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|
|
[PubMed: 23707145]
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[Full Text: https://doi.org/10.1016/S1474-4422(13)70053-X]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C.
|
|
<strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong>
|
|
Nature Genet. 50: 355-361, 2018.
|
|
|
|
|
|
[PubMed: 29403012]
|
|
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|
|
[Full Text: https://doi.org/10.1038/s41588-018-0053-8]
|
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|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others.
|
|
<strong>Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.</strong>
|
|
Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009.
|
|
|
|
|
|
[PubMed: 12612585]
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|
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|
|
[Full Text: https://doi.org/10.1038/ng1121]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Heyne, H. O., Artomov, M., Battke, F., Bianchini, C., Smith, D. R., Liebmann, N., Tadigotla, V., Stanley, C. M., Lal, D., Rehm, H., Lerche, H., Daly, M. J., Helbig, I., Biskup, S., Weber, Y. G., Lemke, J. R.
|
|
<strong>Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy.</strong>
|
|
Genet. Med. 21: 2496-2503, 2019.
|
|
|
|
|
|
[PubMed: 31056551]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41436-019-0531-0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others.
|
|
<strong>CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong>
|
|
Nature Genet. 41: 954-955, 2009.
|
|
|
|
|
|
[PubMed: 19710712]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng0909-954]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Niemeyer, M. I., Cid, L. P., Sepulveda, F. V., Blanz, J., Auberson, M., Jentsch, T. J.
|
|
<strong>No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. (Letter)</strong>
|
|
Nature Genet. 42: 3 only, 2010.
|
|
|
|
|
|
[PubMed: 20037607]
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|
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|
|
|
[Full Text: https://doi.org/10.1038/ng0110-3]
|
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|
|
</p>
|
|
</li>
|
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<li>
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<p class="mim-text-font">
|
|
Niemeyer, M. I., Yusef, Y. R., Cornejo, I., Flores, C. A., Sepulveda, F. V., Cid, L. P.
|
|
<strong>Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.</strong>
|
|
Physiol. Genomics 19: 74-83, 2004.
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|
|
|
|
[PubMed: 15252188]
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|
|
[Full Text: https://doi.org/10.1152/physiolgenomics.00070.2004]
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|
|
</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Saint-Martin, C., Gauvain, G., Teodorescu, G., Gourfinkel-An, I., Fedirko, E., Weber, Y. G., Maljevic, S., Ernst, J.-P., Garcia-Olivares, J., Fahlke, C., Nabbout, R., LeGuern, E., Lerche, H., Poncer, J. C., Depienne, C.
|
|
<strong>Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.</strong>
|
|
Hum. Mutat. 30: 397-405, 2009.
|
|
|
|
|
|
[PubMed: 19191339]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/humu.20876]
|
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|
|
</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Sander, T., Schulz, H., Saar, K., Gennaro, E., Riggio, M. C., Bianchi, A., Zara, F., Luna, D., Bulteau, C., Kaminska, A., Ville, D., Cieuta, C., and 14 others.
|
|
<strong>Genome search for susceptibility loci of common idiopathic generalised epilepsies.</strong>
|
|
Hum. Molec. Genet. 9: 1465-1472, 2000.
|
|
|
|
|
|
[PubMed: 10888596]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/9.10.1465]
|
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|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others.
|
|
<strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong>
|
|
Nature Genet. 50: 349-354, 2018.
|
|
|
|
|
|
[PubMed: 29403011]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41588-018-0048-5]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schwiebert, E. M., Cid-Soto, L. P., Stafford, D., Carter, M., Blaisdell, C. J., Zeitlin, P. L., Guggino, W. B., Cutting, G. R.
|
|
<strong>Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 3879-3884, 1998.
|
|
|
|
|
|
[PubMed: 9520461]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.95.7.3879]
|
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|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sik, A., Smith, R. L., Freund, T. F.
|
|
<strong>Distribution of chloride channel-2-immunoreactive neuronal and astrocytic processes in the hippocampus.</strong>
|
|
Neuroscience 101: 51-65, 2000.
|
|
|
|
|
|
[PubMed: 11068136]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0306-4522(00)00360-2]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stogmann, E., Lichtner, P., Baumgartner, C., Schmied, M., Hotzy, C., Asmus, F., Leutmezer, F., Bonelli, S., Assem-Hilger, E., Vass, K., Hatala, K., Strom, T. M., Meitinger, T., Zimprich, F., Zimprich, A.
|
|
<strong>Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.</strong>
|
|
Neurogenetics 7: 265-268, 2006.
|
|
|
|
|
|
[PubMed: 16932951]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10048-006-0057-x]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L.
|
|
<strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong>
|
|
Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.
|
|
|
|
|
|
[PubMed: 1521363]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1440-1681.1992.tb00462.x]
|
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|
|
</p>
|
|
</li>
|
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<li>
|
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<p class="mim-text-font">
|
|
Stumpf, A. M.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 09/27/2019.
|
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|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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Ada Hamosh - updated : 06/28/2024<br>Anne M. Stumpf - updated : 09/27/2019<br>Cassandra L. Kniffin - updated : 08/09/2018<br>Cassandra L. Kniffin - updated : 2/19/2014<br>Cassandra L. Kniffin - updated : 1/19/2010<br>Cassandra L. Kniffin - updated : 10/2/2009<br>Cassandra L. Kniffin - updated : 12/6/2006<br>Cassandra L. Kniffin - reorganized : 4/9/2003<br>Cassandra L. Kniffin - updated : 3/17/2003<br>Victor A. McKusick - updated : 5/1/1998
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Victor A. McKusick : 6/1/1995
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carol : 06/28/2024<br>alopez : 05/06/2021<br>carol : 09/30/2019<br>alopez : 09/27/2019<br>alopez : 07/15/2019<br>carol : 09/11/2018<br>carol : 08/13/2018<br>carol : 08/10/2018<br>ckniffin : 08/09/2018<br>carol : 02/19/2014<br>mcolton : 2/19/2014<br>ckniffin : 2/19/2014<br>terry : 11/3/2010<br>alopez : 2/1/2010<br>ckniffin : 2/1/2010<br>carol : 1/29/2010<br>alopez : 1/28/2010<br>ckniffin : 1/19/2010<br>carol : 12/24/2009<br>terry : 10/21/2009<br>carol : 10/6/2009<br>ckniffin : 10/2/2009<br>wwang : 12/7/2006<br>ckniffin : 12/6/2006<br>carol : 4/9/2003<br>ckniffin : 3/17/2003<br>alopez : 5/15/1998<br>terry : 5/1/1998<br>mark : 6/1/1995
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