4547 lines
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Entry
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- *604878 - SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER 6; SLC12A6
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- OMIM
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<p>
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<span class="h4">*604878</span>
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<br />
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<strong>Table of Contents</strong>
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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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<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/604878">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li 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 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 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=ENSG00000140199;t=ENST00000354181" 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=9990" 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=604878" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span 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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</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=ENSG00000140199;t=ENST00000354181" 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_001042494,NM_001042495,NM_001042496,NM_001042497,NM_001365088,NM_005135,NM_133647,XM_006720793,XM_011522269,XM_047433396,XR_931960" 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_001365088" 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=604878" 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=09220&isoform_id=09220_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/SLC12A6" 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/4585229,4826780,5106523,5912006,6693798,19110891,22416427,22416428,27151690,33329252,33329254,33329256,57997566,73909166,74319457,110224449,110224452,110224454,110224456,110224458,116496665,116497151,119612701,119612702,119612703,119612704,119612705,119612706,119612707,119612708,133778316,152061007,158258537,189054851,193785577,578827668,767985914,1434520708,2217303493,2462546900,2462546902,2462546905" 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/Q9UHW9" 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=9990" 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=ENSG00000140199;t=ENST00000354181" 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=SLC12A6" 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=SLC12A6" 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+9990" 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/SLC12A6" 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:9990" 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/9990" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr15&hgg_gene=ENST00000354181.8&hgg_start=34229784&hgg_end=34338057&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://medlineplus.gov/genetics/gene/slc12a6" 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=604878[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 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=604878[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://gnomad.broadinstitute.org/gene/ENSG00000140199" 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=SLC12A6" 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=SLC12A6" 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=SLC12A6" 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="http://www.molgen.ua.ac.be/CMTMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SLC12A6&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/PA35808" 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:10914" 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/FBgn0261794.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:2135960" 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/SLC12A6#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:2135960" 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/9990/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002279/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=9990" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00019205;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-160113-148" 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://reactome.org/content/query?q=SLC12A6&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> 702439002<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>
|
|
604878
|
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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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SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER 6; SLC12A6
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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>
|
|
<span class="mim-font">
|
|
POTASSIUM-CHLORIDE COTRANSPORTER 3; KCC3
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
POTASSIUM-CHLORIDE COTRANSPORTER 3, ISOFORM A, INCLUDED; KCC3A, INCLUDED
|
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</span>
|
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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|
|
POTASSIUM-CHLORIDE COTRANSPORTER 3, ISOFORM B, INCLUDED; KCC3B, INCLUDED
|
|
</span>
|
|
</div>
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SLC12A6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SLC12A6</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/15/71?start=-3&limit=10&highlight=71">15q14</a>
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|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:34229784-34338057&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">15:34,229,784-34,338,057</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=218000,620068" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/71?start=-3&limit=10&highlight=71">
|
|
15q14
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Agenesis of the corpus callosum with peripheral neuropathy
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/218000"> 218000 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Cation chloride cotransporters, including the potassium-chloride cotransporters (KCCs), are involved in the electroneutral movement of ions across the plasma membrane. Under most physiologic conditions, KCCs function as efflux pathways (<a href="#2" class="mim-tip-reference" title="Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., Gamble, J. R. <strong>Cloning, characterization, and chromosomal location of a novel human K(+)-Cl(-) cotransporter.</strong> J. Biol. Chem. 274: 10661-10667, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10187864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10187864</a>] [<a href="https://doi.org/10.1074/jbc.274.15.10661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10187864">Hiki et al., 1999</a>; <a href="#6" class="mim-tip-reference" title="Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., Gamba, G. <strong>Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.</strong> J. Biol. Chem. 274: 16355-16362, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10347194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10347194</a>] [<a href="https://doi.org/10.1074/jbc.274.23.16355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10347194">Mount et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10187864+10347194" 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>Using differential display PCR on vascular endothelial cells treated with vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>), <a href="#2" class="mim-tip-reference" title="Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., Gamble, J. R. <strong>Cloning, characterization, and chromosomal location of a novel human K(+)-Cl(-) cotransporter.</strong> J. Biol. Chem. 274: 10661-10667, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10187864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10187864</a>] [<a href="https://doi.org/10.1074/jbc.274.15.10661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10187864">Hiki et al. (1999)</a> identified a cDNA encoding SLC12A6, which they called KCC3. The predicted 1,099-amino acid SLC12A6 protein contains 12 membrane-spanning segments and 5 N-glycosylation sites. SLC12A6 shares 77% amino acid identity with the ubiquitously expressed KCC1 (SLC12A4; <a href="/entry/604119">604119</a>) and 73% identity with the brain-restricted KCC2 (SLC12A5; <a href="/entry/606726">606726</a>). Northern blot analysis detected strong expression of 9-, 7.5-, and 4.5-kb SLC12A6 transcripts in brain, heart, skeletal muscle, and kidney. Western blot analysis showed expression of a 150-kD SLC12A6 protein that was reduced to 120 kD by glycosidase treatment. Functional analyses confirmed that SLC12A6 is a KCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10187864" 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 searching EST databases, <a href="#6" class="mim-tip-reference" title="Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., Gamba, G. <strong>Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.</strong> J. Biol. Chem. 274: 16355-16362, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10347194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10347194</a>] [<a href="https://doi.org/10.1074/jbc.274.23.16355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10347194">Mount et al. (1999)</a> identified a full-length cDNA encoding SLC12A6, which they initially termed KCC4 but later renamed KCC3. This cDNA encodes a deduced 1,150-amino acid protein. Northern blot analysis detected 2 SLC12A6 transcripts of 6- to 7-kb, consistent with alternative splicing, in muscle, brain, lung, heart, and kidney. <a href="#7" class="mim-tip-reference" title="Mount, D. B. <strong>Personal Communication.</strong> Nashville, Tenn. 3/28/2000."None>Mount (2000)</a> designated the longer SLC12A6 isoform KCC3A (<a href="#6" class="mim-tip-reference" title="Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., Gamba, G. <strong>Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.</strong> J. Biol. Chem. 274: 16355-16362, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10347194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10347194</a>] [<a href="https://doi.org/10.1074/jbc.274.23.16355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10347194">Mount et al., 1999</a>) and the shorter SLC12A6 isoform KCC3B (<a href="#2" class="mim-tip-reference" title="Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., Gamble, J. R. <strong>Cloning, characterization, and chromosomal location of a novel human K(+)-Cl(-) cotransporter.</strong> J. Biol. Chem. 274: 10661-10667, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10187864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10187864</a>] [<a href="https://doi.org/10.1074/jbc.274.15.10661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10187864">Hiki et al., 1999</a>). KCC3A is transcribed from a promoter approximately 23 kb 5-prime of KCC3B, and the additional N-terminal sequence contains a cluster of potential protein kinase C phosphorylation sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10347194+10187864" 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="Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., Gamble, J. R. <strong>Cloning, characterization, and chromosomal location of a novel human K(+)-Cl(-) cotransporter.</strong> J. Biol. Chem. 274: 10661-10667, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10187864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10187864</a>] [<a href="https://doi.org/10.1074/jbc.274.15.10661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10187864">Hiki et al. (1999)</a> mapped the SLC12A6 gene to chromosome 15q13 using FISH. By radiation hybrid and somatic cell hybrid analyses, <a href="#6" class="mim-tip-reference" title="Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., Gamba, G. <strong>Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.</strong> J. Biol. Chem. 274: 16355-16362, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10347194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10347194</a>] [<a href="https://doi.org/10.1074/jbc.274.23.16355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10347194">Mount et al. (1999)</a> mapped the SLC12A6 gene to 15q14. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10187864+10347194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Jiao, Y., Jin, X., Yan, J., Zhang, C., Jiao, F., Li, X., Roe, B. A., Mount, D. B., Gu, W. <strong>A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice.</strong> Genomics 91: 407-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18343091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18343091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18343091[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18343091">Jiao et al. (2008)</a> mapped the mouse Slc12a6 gene to chromosome 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18343091" 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>Using a yeast 2-hybrid approach, <a href="#11" class="mim-tip-reference" title="Salin-Cantegrel, A., Shekarabi, M., Holbert, S., Dion, P., Rochefort, D., Laganiere, J., Dacal, S., Hince, P., Karemera, L., Gaspar, C., Lapointe, J.-Y., Rouleau, G. A. <strong>HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.</strong> Hum. Molec. Genet. 17: 2703-2711, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18566107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18566107</a>] [<a href="https://doi.org/10.1093/hmg/ddn172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18566107">Salin-Cantegrel et al. (2008)</a> found that the last 18 amino acids of the C-terminal domain of KCC3 directly interacted with brain-specific creatine kinase (CKB; <a href="/entry/123280">123280</a>), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CKB was confirmed by GST pull-down assay, followed by sequencing of the pulled-down complexes. Studies in transfected cultured cells indicated that CKB colocalized with wildtype KCC3 in vitro. However, mutant KCC3 lacking the C terminus was unable to interact with CKB. Functional studies in Xenopus oocytes showed that an inhibitor of CKB reduced KCC3 transport activity, indicating the proper KCC3 function is dependent on interaction with functional CKB. <a href="#11" class="mim-tip-reference" title="Salin-Cantegrel, A., Shekarabi, M., Holbert, S., Dion, P., Rochefort, D., Laganiere, J., Dacal, S., Hince, P., Karemera, L., Gaspar, C., Lapointe, J.-Y., Rouleau, G. A. <strong>HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.</strong> Hum. Molec. Genet. 17: 2703-2711, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18566107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18566107</a>] [<a href="https://doi.org/10.1093/hmg/ddn172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18566107">Salin-Cantegrel et al. (2008)</a> hypothesized that disruption of ATP trafficking in patients with KCC3 mutations may influence the osmotic integrity of neurons, resulting in neurologic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18566107" 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>Agenesis of the Corpus Callosum with Peripheral Neuropathy</em></strong></p><p>
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The SLC12A6 gene maps to the same region of 15q as agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), also known as Andermann syndrome. ACCPN is transmitted in autosomal recessive fashion and is found at a high frequency in the province of Quebec in Canada. In patients with ACCPN, <a href="#3" class="mim-tip-reference" title="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a> identified 4 distinct protein-truncating mutations in the SLC12A6 gene: 2 in the French Canadian population (<a href="#0001">604878.0001</a>-<a href="#0002">604878.0002</a>) and 2 in non-French Canadian families (<a href="#0003">604878.0003</a>-<a href="#0004">604878.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with Andermann syndrome, <a href="#13" class="mim-tip-reference" title="Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J. <strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong> Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606917</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204181.31175.8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606917">Uyanik et al. (2006)</a> identified 4 different mutations in the SLC12A6 gene (<a href="#0005">604878.0005</a>-<a href="#0008">604878.0008</a>). Two were of Turkish descent and 1 was German. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606917" 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="Salin-Cantegrel, A., Riviere, J.-B., Shekarabi, M., Rasheed, S., DaCal, S., Laganiere, J., Gaudet, R., Rochefort, D., Lesca, G., Gaspar, C., Dion, P. A., Lapointe, J.-Y., Rouleau, G. A. <strong>Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.</strong> J. Biol. Chem. 286: 28456-28465, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21628467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21628467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21628467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.226894" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21628467">Salin-Cantegrel et al. (2011)</a> showed in in vitro studies that mutant SLC12A6 mutations (see, e.g., <a href="#0001">604878.0001</a>; <a href="#0008">604878.0008</a>; <a href="#0010">604878.0010</a>) caused a loss of function by 2 mechanisms, either defective interaction with brain-type creatine kinase or defective trafficking to the plasma membrane. One missense mutation (R207C; <a href="#0008">604878.0008</a>) was retained in the endoplasmic reticulum, and cell treatment with curcumin partially corrected the mislocalization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21628467" 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>Axonal Charcot-Marie-Tooth Disease Type 2II</em></strong></p><p>
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In a 10-year-old boy with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>), <a href="#5" class="mim-tip-reference" title="Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E. <strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong> Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27485015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27485015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27485015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scisignal.aae0546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27485015">Kahle et al. (2016)</a> identified a de novo heterozygous missense mutation in the SLC12A6 gene (T991A; <a href="#0011">604878.0011</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. <a href="#5" class="mim-tip-reference" title="Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E. <strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong> Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27485015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27485015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27485015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scisignal.aae0546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27485015">Kahle et al. (2016)</a> suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27485015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with CMT2II, <a href="#8" class="mim-tip-reference" title="Park, J., Flores, B. R., Scherer, K., Kuepper, H., Rossi, M., Rupprich, K., Rautenberg, M., Deininger, N., Weichselbaum, A., Grimm, A., Sturm, M., Grasshoff, U., Delpire, E., Haack, T. B. <strong>De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.</strong> J. Med. Genet. 57: 283-288, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439721</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31439721">Park et al. (2020)</a> identified de novo heterozygous missense mutations at highly conserved residues in the SLC12A6 gene (R207H; <a href="#0012">604878.0012</a> and Y679C <a href="#0013">604878.0013</a>). The mutations, which were found by trio-based exome sequencing, were not present in public databases, including gnomAD. In vitro functional expression studies in transfected Xenopus oocytes showed that both mutations impaired K+ influx under hypotonic shock compared to controls, consistent with a loss-of-function effect. R207H resulted in a complete loss of function, whereas Y679C caused a partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31439721" 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 11 patients from 7 unrelated Japanese families with CMT2II, <a href="#1" class="mim-tip-reference" title="Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others. <strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong> Ann. Clin. Transl. Neurol. 9: 902-911, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35733399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35733399</a>] [<a href="https://doi.org/10.1002/acn3.51603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35733399">Ando et al. (2022)</a> identified heterozygous mutations in the SLC12A6 gene (see, e.g., <a href="#0012">604878.0012</a>; <a href="#0014">604878.0014</a>-<a href="#0015">604878.0015</a>). There were 3 missense variants and 1 in-frame deletion. The mutations were confirmed by Sanger sequencing and segregated with the disorder in 2 families in which genetic material was available from affected individuals. The mutations occurred de novo in 2 of the families. The mutations occurred throughout the gene, affected highly conserved residues, and were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 2,598 individuals with clinically suspected CMT who underwent genetic studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35733399" 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="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a> found that mice with a targeted deletion of the Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a sensorimotor gating deficit, similar to the human disease. The findings suggested a critical role for SLC12A6 in the development and maintenance of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" 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>Giant axonopathy (gaxp) is an autosomal recessive mutation in mice. Homozygous mutants exhibit ataxia, characteristically lifting their hind legs too high and wobbling side-to-side as they walk. The swollen axons observed in gaxp/gaxp mice have lightly packed organelles, suggesting that swelling is due in part to increased water uptake. <a href="#4" class="mim-tip-reference" title="Jiao, Y., Jin, X., Yan, J., Zhang, C., Jiao, F., Li, X., Roe, B. A., Mount, D. B., Gu, W. <strong>A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice.</strong> Genomics 91: 407-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18343091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18343091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18343091[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18343091">Jiao et al. (2008)</a> identified the gaxp mutation as a 17-base deletion within exon 4 of the Slc12a6 gene. Western blot analysis showed no mutant protein in brain or kidney of gaxp/gaxp mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18343091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E. <strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong> Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27485015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27485015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27485015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scisignal.aae0546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27485015">Kahle et al. (2016)</a> found that CRISPR/Cas9-mediated gene editing used to express the T991A mutation in mice resulted in increased cellular K+ influx due to constitutive activation of the SLC12A6 transporter. Heterozygous mutant mice did not show impaired motor performance, but homozygous mutant mice had significant motor deficits. Electrophysiologic studies showed motor and sensory conduction defects, and peripheral nerve biopsy showed myelination defects, particularly in homozygous mutant animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27485015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 20 French Canadians with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>) from the Charlevoix and Saguenay-Lac-Saint-Jean regions of the province of Quebec in Canada, <a href="#3" class="mim-tip-reference" title="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a> found homozygosity for a guanine deletion in exon 18 at nucleotide 2436 (c.2436delG) of the KCC3A open reading frame. The deletion converted GT at the splice donor site of exon 18 to TA, suggesting an effect on RNA splicing. Furthermore, this splice site mutation was predicted to cause a premature stop codon at amino acid 813, removing the last 338 amino acids from the KCC3 protein (2436delG, Thr813fsTer813). Functional expression studies in Xenopus oocytes showed that the truncated mutant protein was appropriately glycosylated and expressed at the cellular membrane, but was nonfunctional. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" 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>For discussion of the 2436del mutation in the SLC12A6 gene that was found in compound heterozygous state in a patient with ACCPN by <a href="#3" class="mim-tip-reference" title="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a>, see <a href="#0002">604878.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Salin-Cantegrel, A., Riviere, J.-B., Shekarabi, M., Rasheed, S., DaCal, S., Laganiere, J., Gaudet, R., Rochefort, D., Lesca, G., Gaspar, C., Dion, P. A., Lapointe, J.-Y., Rouleau, G. A. <strong>Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.</strong> J. Biol. Chem. 286: 28456-28465, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21628467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21628467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21628467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.226894" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21628467">Salin-Cantegrel et al. (2011)</a> found that the mutant T813X protein had abnormal intracellular localization around the nucleus in brain tissue from a patient with the mutation. The mutant protein was not found in swollen axons. The findings suggested a transit defect of the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21628467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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">rs515726216 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726216;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=rs515726216" 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=rs515726216" 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=RCV000123392" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000123392" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000123392</a>
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<p>In a French Canadian patient with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#3" class="mim-tip-reference" title="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a> found that 1 chromosome 15 allele carried the predominant French Canadian mutation c.2436delG (<a href="#0001">604878.0001</a>) in exon 18, and the other a deletion of adjacent cytosine and thymine nucleotides, along with the insertion of 1 guanine, at positions c.1584 and c.1585 in exon 11 of the SLC12A6 gene. This mutation caused a frameshift and a premature stop codon, predicted to truncate 619 amino acids from the KCC3 protein (Phe529fsTer532). Sequencing both parents indicated that 1 carried the c.2436delG mutation and the other carried the deletion/insertion mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" 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> rs121908427 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908427;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/rs121908427?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=rs121908427" 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=rs121908427" 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=RCV000005652 OR RCV001045170 OR RCV002251882 OR RCV005007826" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005652, RCV001045170, RCV002251882, RCV005007826" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005652...</a>
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<p>In 2 sibs of Turkish origin with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#3" class="mim-tip-reference" title="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a> found a c.3031C-T transition in exon 22 of the SLC12A6 gene, resulting in an arg1011-to-ter (R1011X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" 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="Salin-Cantegrel, A., Riviere, J.-B., Dupre, N., Charron, F. M., Shekarabi, M., Karemera, L., Gaspar, C., Horst, J., Tekin, M., Deda, G., Krause, A., Lippert, M. M., Willemsen, M. A. A. P., Jarrer, R., Lapointe, J.-Y., Rouleau, G. A. <strong>Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.</strong> Neurology 69: 1350-1355, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17893295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17893295</a>] [<a href="https://doi.org/10.1212/01.wnl.0000291779.35643.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17893295">Salin-Cantegrel et al. (2007)</a> identified homozygosity for the R1011X mutation in affected members of 5 unrelated non-French Canadian families with ACCPN. Two families were Afrikaner from South Africa, 2 were from Turkey, and 1 from the Netherlands. Haplotype analysis showed 2 different haplotypes, 1 of which was shared by the Afrikaner and Dutch patients. In vitro functional expression studies showed that the R1011X mutation completely abolished transporter activity, although the mutant protein was weakly expressed at the cell membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893295" 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">rs121908428 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908428;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=rs121908428" 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=rs121908428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sibs of Italian origin with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#3" class="mim-tip-reference" title="Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others. <strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong> Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>] [<a href="https://doi.org/10.1038/ng1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368912">Howard et al. (2002)</a> found a homozygous c.2023C-T transition in exon 15 of the SLC12A6 gene, predicted to result in an arg675-to-ter (R675X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" 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> rs515726217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726217;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/rs515726217?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=rs515726217" 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=rs515726217" 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=RCV000123393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000123393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000123393</a>
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<p>In a 3.5-year-old German girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#13" class="mim-tip-reference" title="Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J. <strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong> Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606917</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204181.31175.8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606917">Uyanik et al. (2006)</a> identified compound heterozygosity for 2 mutations in the SLC12A6 gene: a 1-bp insertion (c.2031insT) and an 8-bp deletion (<a href="#0006">604878.0006</a>). Both mutations were predicted to result in a frameshift and premature termination of the protein. Each unaffected parent was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606917" 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">rs515726218 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726218;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=rs515726218" 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=rs515726218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 3.5-year-old German girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#13" class="mim-tip-reference" title="Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J. <strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong> Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606917</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204181.31175.8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606917">Uyanik et al. (2006)</a> identified compound heterozygosity for 2 mutations in the SLC12A6 gene: an 8-bp deletion (c.1478delTTCCCTCT) and a 1-bp insertion (<a href="#0005">604878.0005</a>). Both mutations were predicted to result in a frameshift and premature termination of the protein. Each unaffected parent was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606917" 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>.0007 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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> rs606231157 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231157;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/rs606231157?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=rs606231157" 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=rs606231157" 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=RCV000005656 OR RCV000790224" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005656, RCV000790224" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005656...</a>
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<p>In a Turkish girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN, <a href="/entry/218000">218000</a>), born of consanguineous parents, <a href="#13" class="mim-tip-reference" title="Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J. <strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong> Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606917</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204181.31175.8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606917">Uyanik et al. (2006)</a> identified a homozygous 1-bp deletion (c.901delA) in the SLC12A6 gene, resulting in premature termination of the protein at codon 315. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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> rs121908429 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908429;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/rs121908429?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=rs121908429" 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=rs121908429" 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=RCV000005657 OR RCV000790223 OR RCV002512812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005657, RCV000790223, RCV002512812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005657...</a>
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<p>In a 10.5-year-old Turkish boy with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), born of consanguineous parents, <a href="#13" class="mim-tip-reference" title="Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J. <strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong> Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606917</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204181.31175.8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606917">Uyanik et al. (2006)</a> identified a homozygous c.619C-T transition in the SLC12A6 gene, resulting in an arg207-to-cys (R207C) substitution. This patient had slightly less severe neuropathy and also had white matter abnormalities not previously reported in this disorder. The authors noted that this was the first SLC12A6 missense mutation associated with ACCPN and postulated that a dysfunctional SLC12A6 protein may lead to a different phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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By in vitro studies in mammalian cells, <a href="#10" class="mim-tip-reference" title="Salin-Cantegrel, A., Riviere, J.-B., Shekarabi, M., Rasheed, S., DaCal, S., Laganiere, J., Gaudet, R., Rochefort, D., Lesca, G., Gaspar, C., Dion, P. A., Lapointe, J.-Y., Rouleau, G. A. <strong>Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.</strong> J. Biol. Chem. 286: 28456-28465, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21628467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21628467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21628467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.226894" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21628467">Salin-Cantegrel et al. (2011)</a> demonstrated that the R207C mutant protein interacted with brain-type creatine kinase (CKB; <a href="/entry/123280">123280</a>), but had decreased transport activity when expressed in Xenopus oocytes. The mutant protein showed strong localization to the perinuclear region and endoplasmic reticulum, as well as poor membrane localization when expressed in HeLa cells, suggesting a trafficking defect. Western blot analysis showed that the mutant R207C protein also formed stable homodimers, which may have affected transit to the plasma membrane. Treatment with curcumin partially corrected the mislocalization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21628467" 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">rs606231158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231158;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=rs606231158" 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=rs606231158" 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=RCV000005658 OR RCV000790221" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005658, RCV000790221" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005658...</a>
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<p>In 2 brothers, born of consanguineous Sudanese parents, with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#9" class="mim-tip-reference" title="Salin-Cantegrel, A., Riviere, J.-B., Dupre, N., Charron, F. M., Shekarabi, M., Karemera, L., Gaspar, C., Horst, J., Tekin, M., Deda, G., Krause, A., Lippert, M. M., Willemsen, M. A. A. P., Jarrer, R., Lapointe, J.-Y., Rouleau, G. A. <strong>Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.</strong> Neurology 69: 1350-1355, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17893295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17893295</a>] [<a href="https://doi.org/10.1212/01.wnl.0000291779.35643.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17893295">Salin-Cantegrel et al. (2007)</a> identified a homozygous 10-bp deletion (nucleotides 2995 to 3003) in exon 22 of the SLC12A6 gene, resulting in a frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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> rs606231229 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231229;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/rs606231229?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=rs606231229" 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=rs606231229" 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=RCV000023393 OR RCV000790222" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023393, RCV000790222" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023393...</a>
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<p>In affected members of a consanguineous Algerian family with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; <a href="/entry/218000">218000</a>), <a href="#10" class="mim-tip-reference" title="Salin-Cantegrel, A., Riviere, J.-B., Shekarabi, M., Rasheed, S., DaCal, S., Laganiere, J., Gaudet, R., Rochefort, D., Lesca, G., Gaspar, C., Dion, P. A., Lapointe, J.-Y., Rouleau, G. A. <strong>Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.</strong> J. Biol. Chem. 286: 28456-28465, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21628467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21628467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21628467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.226894" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21628467">Salin-Cantegrel et al. (2011)</a> identified a homozygous c.3402C-T transition in exon 25 of the SLC12A6 gene, resulting in an arg1134-to-ter (R1134X) substitution and a truncated protein missing only the last 17 residues. In vitro immunofluorescence studies in HeLa cells showed that the mutant truncated protein did not interact properly with brain-type creatine kinase (CKB; <a href="/entry/123280">123280</a>) and did not have transport activity when expressed in Xenopus oocytes, consistent with a loss of function. The mutant protein also showed abnormal localization within the cytoplasm, not at the cell membrane, suggesting a defect in trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21628467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002287912 OR RCV003134422 OR RCV004801189" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002287912, RCV003134422, RCV004801189" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002287912...</a>
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<p>In a 10-year-old boy with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>), <a href="#5" class="mim-tip-reference" title="Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E. <strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong> Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27485015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27485015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27485015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scisignal.aae0546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27485015">Kahle et al. (2016)</a> identified a de novo heterozygous c.2971A-G transition (c.2971A-G, NM_133647.1) in exon 22 of the SLC12A6 gene, resulting in a thr991-to-ala (T991A) substitution at a highly conserved residue in the cytoplasmic C-terminal regulatory site of SLC12A6 activity. The mutation, which was found by trio-based whole-exome sequencing, was not present in major public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. <a href="#5" class="mim-tip-reference" title="Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E. <strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong> Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27485015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27485015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27485015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scisignal.aae0546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27485015">Kahle et al. (2016)</a> suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27485015" 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</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">rs1555381416 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555381416;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=rs1555381416" 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=rs1555381416" 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=RCV000623060 OR RCV002287895 OR RCV002532836" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000623060, RCV002287895, RCV002532836" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000623060...</a>
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<p>In 2 unrelated boys (P1 and P2) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>), <a href="#8" class="mim-tip-reference" title="Park, J., Flores, B. R., Scherer, K., Kuepper, H., Rossi, M., Rupprich, K., Rautenberg, M., Deininger, N., Weichselbaum, A., Grimm, A., Sturm, M., Grasshoff, U., Delpire, E., Haack, T. B. <strong>De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.</strong> J. Med. Genet. 57: 283-288, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439721</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31439721">Park et al. (2020)</a> identified a de novo heterozygous c.620G-A transition (c.620G-A, NM_133647.1) in the SLC12A6 gene, resulting in an arg207-to-his (R207H) substitution at a highly conserved residue. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed impaired K+ influx under hypotonic shock compared to controls, consistent with a complete loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31439721" 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 31-year-old Chinese man with CMT2II, <a href="#12" class="mim-tip-reference" title="Shi, J., Zhao, F., Pang, X., Huang, S., Wang, J., Chang, X., Zhang, J., Liu, Y., Guo, J., Zhang, W. <strong>Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy.</strong> Neuromusc. Disord. 31: 149-157, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33323309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33323309</a>] [<a href="https://doi.org/10.1016/j.nmd.2020.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33323309">Shi et al. (2021)</a> identified a heterozygous R207H mutation in exon 5 of the SLC12A6 gene. The mutation was found by whole-exome sequencing and was not present in public databases, including dbSNP and gnomAD. Functional studies of the variant were not performed, but molecular modeling suggested that it may interfere with homo- or heterodimer formation and cause a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33323309" 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="Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others. <strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong> Ann. Clin. Transl. Neurol. 9: 902-911, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35733399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35733399</a>] [<a href="https://doi.org/10.1002/acn3.51603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35733399">Ando et al. (2022)</a> identified a de novo heterozygous R207H mutation in an 8-year-old Japanese girl (patient 1) with CMT2II. Functional studies of the variant and studies of patient cells were not performed. The patient also had progressive visual loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35733399" 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">rs2140682156 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2140682156;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=rs2140682156" 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=rs2140682156" 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=RCV001939422 OR RCV002287901" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001939422, RCV002287901" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001939422...</a>
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<p>In a 15-year-old girl (patient 3) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>), <a href="#8" class="mim-tip-reference" title="Park, J., Flores, B. R., Scherer, K., Kuepper, H., Rossi, M., Rupprich, K., Rautenberg, M., Deininger, N., Weichselbaum, A., Grimm, A., Sturm, M., Grasshoff, U., Delpire, E., Haack, T. B. <strong>De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.</strong> J. Med. Genet. 57: 283-288, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439721</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31439721">Park et al. (2020)</a> identified a de novo heterozygous c.2036A-G transition (c.2036A-G, NM_133647.1) in the SLC12A6 gene, resulting in a tyr679-to-cys (Y679C) substitution. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed impaired K+ influx under hypotonic shock compared to controls, consistent with a partial loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31439721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 4 affected members of a Japanese family (family 2) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>) <a href="#1" class="mim-tip-reference" title="Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others. <strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong> Ann. Clin. Transl. Neurol. 9: 902-911, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35733399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35733399</a>] [<a href="https://doi.org/10.1002/acn3.51603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35733399">Ando et al. (2022)</a> identified a heterozygous c.865G-A transition (c.865G-A, NM_133647) in the SLC12A6 gene, resulting in a glu289-to-lys (E289K) substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family. The same heterozygous E289K mutation was found in a 40-year-old Japanese woman (family 3) who had onset of the disorder at 10 years of age. Her mother, sister, and son were similarly affected, but DNA was not available for familial segregation studies. The mutation was not present in the gnomAD database; functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35733399" 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</strong>
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SLC12A6, 3-BP DEL, 1731CTT
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002287914 OR RCV003101653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002287914, RCV003101653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002287914...</a>
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<p>In 3 unrelated Japanese patients (families 4, 5, and 6) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>), <a href="#1" class="mim-tip-reference" title="Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others. <strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong> Ann. Clin. Transl. Neurol. 9: 902-911, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35733399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35733399</a>] [<a href="https://doi.org/10.1002/acn3.51603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35733399">Ando et al. (2022)</a> identified a heterozygous 3-bp in-frame deletion (c.1731delCTT, NM_133647) in the SLC12A6 gene, resulting in the deletion of conserved residue phe578 (Phe578del). The mutation, which was confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was demonstrated to be inherited from the affected father in family 4, consistent with autosomal dominant inheritance. There were additional affected family members in families 5 and 6, but genetic analysis was performed only for the probands. Functional studies of the variant and studies of patient cells were not performed. The authors noted that patients with this mutation had a slightly later age at onset, between 19 and 40 years, compared to patients with other mutations who had onset in the first decade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35733399" 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>.0016 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002287915" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002287915" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002287915</a>
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<p>In a 26-year-old Japanese woman (patient 7) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; <a href="/entry/620068">620068</a>), <a href="#1" class="mim-tip-reference" title="Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others. <strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong> Ann. Clin. Transl. Neurol. 9: 902-911, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35733399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35733399</a>] [<a href="https://doi.org/10.1002/acn3.51603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35733399">Ando et al. (2022)</a> identified a de novo heterozygous c.2036A-C transversion (c.2036A-C, NM_133647) in the SLC12A6 gene, resulting in a tyr679-to-ser (Y679S) substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. In addition to peripheral neuropathy, the patient had impaired intellectual development (IQ of 46), seizures, frontal and temporal lobe atrophy on brain imaging, and hemolytic anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35733399" 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="Ando2022" class="mim-anchor"></a>
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Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others.
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<strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong>
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Ann. Clin. Transl. Neurol. 9: 902-911, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35733399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35733399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35733399" 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/acn3.51603" target="_blank">Full Text</a>]
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Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., Gamble, J. R.
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<strong>Cloning, characterization, and chromosomal location of a novel human K(+)-Cl(-) cotransporter.</strong>
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J. Biol. Chem. 274: 10661-10667, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10187864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10187864</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10187864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.274.15.10661" target="_blank">Full Text</a>]
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Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others.
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<strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong>
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Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368912</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368912" 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/ng1002" target="_blank">Full Text</a>]
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Jiao, Y., Jin, X., Yan, J., Zhang, C., Jiao, F., Li, X., Roe, B. A., Mount, D. B., Gu, W.
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<strong>A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice.</strong>
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Genomics 91: 407-414, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18343091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18343091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18343091[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=18343091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ygeno.2007.12.010" target="_blank">Full Text</a>]
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Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E.
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<strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong>
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Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27485015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27485015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27485015[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=27485015" 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/10.1126/scisignal.aae0546" target="_blank">Full Text</a>]
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<a id="Mount1999" class="mim-anchor"></a>
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Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., Gamba, G.
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<strong>Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.</strong>
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J. Biol. Chem. 274: 16355-16362, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10347194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10347194</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10347194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.274.23.16355" target="_blank">Full Text</a>]
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Mount, D. B.
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<strong>Personal Communication.</strong>
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Nashville, Tenn. 3/28/2000.
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Park, J., Flores, B. R., Scherer, K., Kuepper, H., Rossi, M., Rupprich, K., Rautenberg, M., Deininger, N., Weichselbaum, A., Grimm, A., Sturm, M., Grasshoff, U., Delpire, E., Haack, T. B.
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<strong>De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.</strong>
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J. Med. Genet. 57: 283-288, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31439721" 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/10.1136/jmedgenet-2019-106273" target="_blank">Full Text</a>]
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Salin-Cantegrel, A., Riviere, J.-B., Dupre, N., Charron, F. M., Shekarabi, M., Karemera, L., Gaspar, C., Horst, J., Tekin, M., Deda, G., Krause, A., Lippert, M. M., Willemsen, M. A. A. P., Jarrer, R., Lapointe, J.-Y., Rouleau, G. A.
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<strong>Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.</strong>
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Neurology 69: 1350-1355, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17893295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17893295</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000291779.35643.15" target="_blank">Full Text</a>]
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Salin-Cantegrel, A., Riviere, J.-B., Shekarabi, M., Rasheed, S., DaCal, S., Laganiere, J., Gaudet, R., Rochefort, D., Lesca, G., Gaspar, C., Dion, P. A., Lapointe, J.-Y., Rouleau, G. A.
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<strong>Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.</strong>
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J. Biol. Chem. 286: 28456-28465, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21628467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21628467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21628467[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=21628467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M111.226894" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Salin-Cantegrel2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Salin-Cantegrel, A., Shekarabi, M., Holbert, S., Dion, P., Rochefort, D., Laganiere, J., Dacal, S., Hince, P., Karemera, L., Gaspar, C., Lapointe, J.-Y., Rouleau, G. A.
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<strong>HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.</strong>
|
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Hum. Molec. Genet. 17: 2703-2711, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18566107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18566107</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18566107" 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/ddn172" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Shi2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shi, J., Zhao, F., Pang, X., Huang, S., Wang, J., Chang, X., Zhang, J., Liu, Y., Guo, J., Zhang, W.
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<strong>Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy.</strong>
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Neuromusc. Disord. 31: 149-157, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33323309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33323309</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33323309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2020.11.002" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Uyanik2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J.
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<strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong>
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Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606917</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000204181.31175.8b" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/05/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/11/2011<br>Cassandra L. Kniffin - updated : 7/29/2010<br>Patricia A. Hartz - updated : 6/6/2008<br>Cassandra L. Kniffin - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 7/25/2007<br>Victor A. McKusick - updated : 10/4/2002
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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="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 4/26/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/09/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/08/2024<br>alopez : 10/07/2022<br>ckniffin : 10/05/2022<br>carol : 09/15/2016<br>alopez : 03/16/2016<br>carol : 11/26/2014<br>carol : 9/16/2013<br>terry : 6/6/2012<br>terry : 10/26/2011<br>carol : 10/14/2011<br>terry : 10/12/2011<br>ckniffin : 10/11/2011<br>wwang : 8/5/2010<br>ckniffin : 7/29/2010<br>mgross : 6/11/2008<br>mgross : 6/11/2008<br>terry : 6/6/2008<br>wwang : 4/7/2008<br>ckniffin : 3/31/2008<br>wwang : 8/2/2007<br>ckniffin : 7/25/2007<br>cwells : 11/12/2003<br>alopez : 1/16/2003<br>alopez : 11/7/2002<br>cwells : 10/7/2002<br>terry : 10/4/2002<br>mgross : 4/26/2000
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</span>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604878
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER 6; SLC12A6
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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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<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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POTASSIUM-CHLORIDE COTRANSPORTER 3; KCC3
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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POTASSIUM-CHLORIDE COTRANSPORTER 3, ISOFORM A, INCLUDED; KCC3A, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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POTASSIUM-CHLORIDE COTRANSPORTER 3, ISOFORM B, INCLUDED; KCC3B, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SLC12A6</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 702439002;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 15q14
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:34,229,784-34,338,057 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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15q14
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</span>
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</td>
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<td>
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<span class="mim-font">
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Agenesis of the corpus callosum with peripheral neuropathy
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
218000
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2II
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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620068
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
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|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Cation chloride cotransporters, including the potassium-chloride cotransporters (KCCs), are involved in the electroneutral movement of ions across the plasma membrane. Under most physiologic conditions, KCCs function as efflux pathways (Hiki et al., 1999; Mount et al., 1999). </p>
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
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</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>Using differential display PCR on vascular endothelial cells treated with vascular endothelial growth factor (VEGF; 192240), Hiki et al. (1999) identified a cDNA encoding SLC12A6, which they called KCC3. The predicted 1,099-amino acid SLC12A6 protein contains 12 membrane-spanning segments and 5 N-glycosylation sites. SLC12A6 shares 77% amino acid identity with the ubiquitously expressed KCC1 (SLC12A4; 604119) and 73% identity with the brain-restricted KCC2 (SLC12A5; 606726). Northern blot analysis detected strong expression of 9-, 7.5-, and 4.5-kb SLC12A6 transcripts in brain, heart, skeletal muscle, and kidney. Western blot analysis showed expression of a 150-kD SLC12A6 protein that was reduced to 120 kD by glycosidase treatment. Functional analyses confirmed that SLC12A6 is a KCC. </p><p>By searching EST databases, Mount et al. (1999) identified a full-length cDNA encoding SLC12A6, which they initially termed KCC4 but later renamed KCC3. This cDNA encodes a deduced 1,150-amino acid protein. Northern blot analysis detected 2 SLC12A6 transcripts of 6- to 7-kb, consistent with alternative splicing, in muscle, brain, lung, heart, and kidney. Mount (2000) designated the longer SLC12A6 isoform KCC3A (Mount et al., 1999) and the shorter SLC12A6 isoform KCC3B (Hiki et al., 1999). KCC3A is transcribed from a promoter approximately 23 kb 5-prime of KCC3B, and the additional N-terminal sequence contains a cluster of potential protein kinase C phosphorylation sites. </p>
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</span>
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<div>
|
|
<br />
|
|
</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Hiki et al. (1999) mapped the SLC12A6 gene to chromosome 15q13 using FISH. By radiation hybrid and somatic cell hybrid analyses, Mount et al. (1999) mapped the SLC12A6 gene to 15q14. </p><p>Jiao et al. (2008) mapped the mouse Slc12a6 gene to chromosome 2. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Using a yeast 2-hybrid approach, Salin-Cantegrel et al. (2008) found that the last 18 amino acids of the C-terminal domain of KCC3 directly interacted with brain-specific creatine kinase (CKB; 123280), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CKB was confirmed by GST pull-down assay, followed by sequencing of the pulled-down complexes. Studies in transfected cultured cells indicated that CKB colocalized with wildtype KCC3 in vitro. However, mutant KCC3 lacking the C terminus was unable to interact with CKB. Functional studies in Xenopus oocytes showed that an inhibitor of CKB reduced KCC3 transport activity, indicating the proper KCC3 function is dependent on interaction with functional CKB. Salin-Cantegrel et al. (2008) hypothesized that disruption of ATP trafficking in patients with KCC3 mutations may influence the osmotic integrity of neurons, resulting in neurologic disease. </p>
|
|
</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Agenesis of the Corpus Callosum with Peripheral Neuropathy</em></strong></p><p>
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The SLC12A6 gene maps to the same region of 15q as agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), also known as Andermann syndrome. ACCPN is transmitted in autosomal recessive fashion and is found at a high frequency in the province of Quebec in Canada. In patients with ACCPN, Howard et al. (2002) identified 4 distinct protein-truncating mutations in the SLC12A6 gene: 2 in the French Canadian population (604878.0001-604878.0002) and 2 in non-French Canadian families (604878.0003-604878.0004). </p><p>In 3 unrelated patients with Andermann syndrome, Uyanik et al. (2006) identified 4 different mutations in the SLC12A6 gene (604878.0005-604878.0008). Two were of Turkish descent and 1 was German. </p><p>Salin-Cantegrel et al. (2011) showed in in vitro studies that mutant SLC12A6 mutations (see, e.g., 604878.0001; 604878.0008; 604878.0010) caused a loss of function by 2 mechanisms, either defective interaction with brain-type creatine kinase or defective trafficking to the plasma membrane. One missense mutation (R207C; 604878.0008) was retained in the endoplasmic reticulum, and cell treatment with curcumin partially corrected the mislocalization. </p><p><strong><em>Axonal Charcot-Marie-Tooth Disease Type 2II</em></strong></p><p>
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|
In a 10-year-old boy with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Kahle et al. (2016) identified a de novo heterozygous missense mutation in the SLC12A6 gene (T991A; 604878.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. Kahle et al. (2016) suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability. </p><p>In 3 unrelated patients with CMT2II, Park et al. (2020) identified de novo heterozygous missense mutations at highly conserved residues in the SLC12A6 gene (R207H; 604878.0012 and Y679C 604878.0013). The mutations, which were found by trio-based exome sequencing, were not present in public databases, including gnomAD. In vitro functional expression studies in transfected Xenopus oocytes showed that both mutations impaired K+ influx under hypotonic shock compared to controls, consistent with a loss-of-function effect. R207H resulted in a complete loss of function, whereas Y679C caused a partial loss of function. </p><p>In 11 patients from 7 unrelated Japanese families with CMT2II, Ando et al. (2022) identified heterozygous mutations in the SLC12A6 gene (see, e.g., 604878.0012; 604878.0014-604878.0015). There were 3 missense variants and 1 in-frame deletion. The mutations were confirmed by Sanger sequencing and segregated with the disorder in 2 families in which genetic material was available from affected individuals. The mutations occurred de novo in 2 of the families. The mutations occurred throughout the gene, affected highly conserved residues, and were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 2,598 individuals with clinically suspected CMT who underwent genetic studies. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Howard et al. (2002) found that mice with a targeted deletion of the Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a sensorimotor gating deficit, similar to the human disease. The findings suggested a critical role for SLC12A6 in the development and maintenance of the nervous system. </p><p>Giant axonopathy (gaxp) is an autosomal recessive mutation in mice. Homozygous mutants exhibit ataxia, characteristically lifting their hind legs too high and wobbling side-to-side as they walk. The swollen axons observed in gaxp/gaxp mice have lightly packed organelles, suggesting that swelling is due in part to increased water uptake. Jiao et al. (2008) identified the gaxp mutation as a 17-base deletion within exon 4 of the Slc12a6 gene. Western blot analysis showed no mutant protein in brain or kidney of gaxp/gaxp mice. </p><p>Kahle et al. (2016) found that CRISPR/Cas9-mediated gene editing used to express the T991A mutation in mice resulted in increased cellular K+ influx due to constitutive activation of the SLC12A6 transporter. Heterozygous mutant mice did not show impaired motor performance, but homozygous mutant mice had significant motor deficits. Electrophysiologic studies showed motor and sensory conduction defects, and peripheral nerve biopsy showed myelination defects, particularly in homozygous mutant animals. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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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SLC12A6, 1-BP DEL, 2436G
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<br />
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SNP: rs515726215,
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ClinVar: RCV000499636, RCV000790219, RCV001357809, RCV004752923, RCV005010437
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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 20 French Canadians with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000) from the Charlevoix and Saguenay-Lac-Saint-Jean regions of the province of Quebec in Canada, Howard et al. (2002) found homozygosity for a guanine deletion in exon 18 at nucleotide 2436 (c.2436delG) of the KCC3A open reading frame. The deletion converted GT at the splice donor site of exon 18 to TA, suggesting an effect on RNA splicing. Furthermore, this splice site mutation was predicted to cause a premature stop codon at amino acid 813, removing the last 338 amino acids from the KCC3 protein (2436delG, Thr813fsTer813). Functional expression studies in Xenopus oocytes showed that the truncated mutant protein was appropriately glycosylated and expressed at the cellular membrane, but was nonfunctional. </p><p>For discussion of the 2436del mutation in the SLC12A6 gene that was found in compound heterozygous state in a patient with ACCPN by Howard et al. (2002), see 604878.0002. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Salin-Cantegrel et al. (2011) found that the mutant T813X protein had abnormal intracellular localization around the nucleus in brain tissue from a patient with the mutation. The mutant protein was not found in swollen axons. The findings suggested a transit defect of the mutant protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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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SLC12A6, 2-BP DEL, 1584CT AND 1-BP INS, 1584G
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<br />
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|
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SNP: rs515726216,
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ClinVar: RCV000123392
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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 French Canadian patient with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Howard et al. (2002) found that 1 chromosome 15 allele carried the predominant French Canadian mutation c.2436delG (604878.0001) in exon 18, and the other a deletion of adjacent cytosine and thymine nucleotides, along with the insertion of 1 guanine, at positions c.1584 and c.1585 in exon 11 of the SLC12A6 gene. This mutation caused a frameshift and a premature stop codon, predicted to truncate 619 amino acids from the KCC3 protein (Phe529fsTer532). Sequencing both parents indicated that 1 carried the c.2436delG mutation and the other carried the deletion/insertion mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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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SLC12A6, ARG1011TER
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<br />
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SNP: rs121908427,
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gnomAD: rs121908427,
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ClinVar: RCV000005652, RCV001045170, RCV002251882, RCV005007826
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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 Turkish origin with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Howard et al. (2002) found a c.3031C-T transition in exon 22 of the SLC12A6 gene, resulting in an arg1011-to-ter (R1011X) substitution. </p><p>Salin-Cantegrel et al. (2007) identified homozygosity for the R1011X mutation in affected members of 5 unrelated non-French Canadian families with ACCPN. Two families were Afrikaner from South Africa, 2 were from Turkey, and 1 from the Netherlands. Haplotype analysis showed 2 different haplotypes, 1 of which was shared by the Afrikaner and Dutch patients. In vitro functional expression studies showed that the R1011X mutation completely abolished transporter activity, although the mutant protein was weakly expressed at the cell membrane. </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>.0004 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
SLC12A6, ARG675TER
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|
<br />
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|
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SNP: rs121908428,
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|
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ClinVar: RCV000005653, RCV001045904, RCV004730835
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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 Italian origin with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Howard et al. (2002) found a homozygous c.2023C-T transition in exon 15 of the SLC12A6 gene, predicted to result in an arg675-to-ter (R675X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC12A6, 1-BP INS, 2031T
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|
|
|
<br />
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|
|
SNP: rs515726217,
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|
|
gnomAD: rs515726217,
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|
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ClinVar: RCV000123393
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|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3.5-year-old German girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Uyanik et al. (2006) identified compound heterozygosity for 2 mutations in the SLC12A6 gene: a 1-bp insertion (c.2031insT) and an 8-bp deletion (604878.0006). Both mutations were predicted to result in a frameshift and premature termination of the protein. Each unaffected parent was heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
|
SLC12A6, 8-BP DEL, NT1478
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|
|
|
<br />
|
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|
|
SNP: rs515726218,
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|
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|
|
ClinVar: RCV000123394
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|
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</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3.5-year-old German girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Uyanik et al. (2006) identified compound heterozygosity for 2 mutations in the SLC12A6 gene: an 8-bp deletion (c.1478delTTCCCTCT) and a 1-bp insertion (604878.0005). Both mutations were predicted to result in a frameshift and premature termination of the protein. Each unaffected parent was heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
SLC12A6, 1-BP DEL, 901A
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|
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<br />
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|
|
SNP: rs606231157,
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|
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gnomAD: rs606231157,
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|
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ClinVar: RCV000005656, RCV000790224
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|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN, 218000), born of consanguineous parents, Uyanik et al. (2006) identified a homozygous 1-bp deletion (c.901delA) in the SLC12A6 gene, resulting in premature termination of the protein at codon 315. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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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|
|
SLC12A6, ARG207CYS
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<br />
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|
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SNP: rs121908429,
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|
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gnomAD: rs121908429,
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ClinVar: RCV000005657, RCV000790223, RCV002512812
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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 10.5-year-old Turkish boy with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), born of consanguineous parents, Uyanik et al. (2006) identified a homozygous c.619C-T transition in the SLC12A6 gene, resulting in an arg207-to-cys (R207C) substitution. This patient had slightly less severe neuropathy and also had white matter abnormalities not previously reported in this disorder. The authors noted that this was the first SLC12A6 missense mutation associated with ACCPN and postulated that a dysfunctional SLC12A6 protein may lead to a different phenotype. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
By in vitro studies in mammalian cells, Salin-Cantegrel et al. (2011) demonstrated that the R207C mutant protein interacted with brain-type creatine kinase (CKB; 123280), but had decreased transport activity when expressed in Xenopus oocytes. The mutant protein showed strong localization to the perinuclear region and endoplasmic reticulum, as well as poor membrane localization when expressed in HeLa cells, suggesting a trafficking defect. Western blot analysis showed that the mutant R207C protein also formed stable homodimers, which may have affected transit to the plasma membrane. Treatment with curcumin partially corrected the mislocalization. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</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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SLC12A6, 10-BP DEL, NT2994
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<br />
|
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|
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SNP: rs606231158,
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ClinVar: RCV000005658, RCV000790221
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 2 brothers, born of consanguineous Sudanese parents, with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Salin-Cantegrel et al. (2007) identified a homozygous 10-bp deletion (nucleotides 2995 to 3003) in exon 22 of the SLC12A6 gene, resulting in a frameshift and premature termination. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
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SLC12A6, ARG1134TER
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<br />
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SNP: rs606231229,
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gnomAD: rs606231229,
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ClinVar: RCV000023393, RCV000790222
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a consanguineous Algerian family with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Salin-Cantegrel et al. (2011) identified a homozygous c.3402C-T transition in exon 25 of the SLC12A6 gene, resulting in an arg1134-to-ter (R1134X) substitution and a truncated protein missing only the last 17 residues. In vitro immunofluorescence studies in HeLa cells showed that the mutant truncated protein did not interact properly with brain-type creatine kinase (CKB; 123280) and did not have transport activity when expressed in Xenopus oocytes, consistent with a loss of function. The mutant protein also showed abnormal localization within the cytoplasm, not at the cell membrane, suggesting a defect in trafficking. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</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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SLC12A6, THR991ALA
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<br />
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ClinVar: RCV002287912, RCV003134422, RCV004801189
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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 10-year-old boy with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Kahle et al. (2016) identified a de novo heterozygous c.2971A-G transition (c.2971A-G, NM_133647.1) in exon 22 of the SLC12A6 gene, resulting in a thr991-to-ala (T991A) substitution at a highly conserved residue in the cytoplasmic C-terminal regulatory site of SLC12A6 activity. The mutation, which was found by trio-based whole-exome sequencing, was not present in major public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. Kahle et al. (2016) suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability. </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>.0012 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</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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SLC12A6, ARG207HIS
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<br />
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SNP: rs1555381416,
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ClinVar: RCV000623060, RCV002287895, RCV002532836
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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 2 unrelated boys (P1 and P2) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Park et al. (2020) identified a de novo heterozygous c.620G-A transition (c.620G-A, NM_133647.1) in the SLC12A6 gene, resulting in an arg207-to-his (R207H) substitution at a highly conserved residue. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed impaired K+ influx under hypotonic shock compared to controls, consistent with a complete loss-of-function effect. </p><p>In a 31-year-old Chinese man with CMT2II, Shi et al. (2021) identified a heterozygous R207H mutation in exon 5 of the SLC12A6 gene. The mutation was found by whole-exome sequencing and was not present in public databases, including dbSNP and gnomAD. Functional studies of the variant were not performed, but molecular modeling suggested that it may interfere with homo- or heterodimer formation and cause a dominant-negative effect. </p><p>Ando et al. (2022) identified a de novo heterozygous R207H mutation in an 8-year-old Japanese girl (patient 1) with CMT2II. Functional studies of the variant and studies of patient cells were not performed. The patient also had progressive visual loss. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</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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SLC12A6, TYR679CYS
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<br />
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SNP: rs2140682156,
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ClinVar: RCV001939422, RCV002287901
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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 15-year-old girl (patient 3) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Park et al. (2020) identified a de novo heterozygous c.2036A-G transition (c.2036A-G, NM_133647.1) in the SLC12A6 gene, resulting in a tyr679-to-cys (Y679C) substitution. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed impaired K+ influx under hypotonic shock compared to controls, consistent with a partial loss-of-function effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</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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SLC12A6, GLU289LYS
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<br />
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ClinVar: RCV002287913
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected members of a Japanese family (family 2) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068) Ando et al. (2022) identified a heterozygous c.865G-A transition (c.865G-A, NM_133647) in the SLC12A6 gene, resulting in a glu289-to-lys (E289K) substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family. The same heterozygous E289K mutation was found in a 40-year-old Japanese woman (family 3) who had onset of the disorder at 10 years of age. Her mother, sister, and son were similarly affected, but DNA was not available for familial segregation studies. The mutation was not present in the gnomAD database; functional studies of the variant and studies of patient cells were not performed. </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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</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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SLC12A6, 3-BP DEL, 1731CTT
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<br />
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ClinVar: RCV002287914, RCV003101653
|
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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 3 unrelated Japanese patients (families 4, 5, and 6) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Ando et al. (2022) identified a heterozygous 3-bp in-frame deletion (c.1731delCTT, NM_133647) in the SLC12A6 gene, resulting in the deletion of conserved residue phe578 (Phe578del). The mutation, which was confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was demonstrated to be inherited from the affected father in family 4, consistent with autosomal dominant inheritance. There were additional affected family members in families 5 and 6, but genetic analysis was performed only for the probands. Functional studies of the variant and studies of patient cells were not performed. The authors noted that patients with this mutation had a slightly later age at onset, between 19 and 40 years, compared to patients with other mutations who had onset in the first decade. </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>.0016 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
SLC12A6, TYR679SER
|
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|
|
<br />
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|
|
|
ClinVar: RCV002287915
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old Japanese woman (patient 7) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Ando et al. (2022) identified a de novo heterozygous c.2036A-C transversion (c.2036A-C, NM_133647) in the SLC12A6 gene, resulting in a tyr679-to-ser (Y679S) substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. In addition to peripheral neuropathy, the patient had impaired intellectual development (IQ of 46), seizures, frontal and temporal lobe atrophy on brain imaging, and hemolytic anemia. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
|
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</h4>
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<div>
|
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Ando, M., Higuchi, Y., Yuan, J., Yoshimura, A., Taniguchi, T., Takei, J., Takeuchi, M., Hiramatsu, Y., Shimizu, F., Kubota, M., Takeshima, A., Ueda, T., and 10 others.
|
|
<strong>Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.</strong>
|
|
Ann. Clin. Transl. Neurol. 9: 902-911, 2022.
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[PubMed: 35733399]
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[Full Text: https://doi.org/10.1002/acn3.51603]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., Gamble, J. R.
|
|
<strong>Cloning, characterization, and chromosomal location of a novel human K(+)-Cl(-) cotransporter.</strong>
|
|
J. Biol. Chem. 274: 10661-10667, 1999.
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[PubMed: 10187864]
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[Full Text: https://doi.org/10.1074/jbc.274.15.10661]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.-B., Prevost, C., Horst, J., Simonati, A., and 12 others.
|
|
<strong>The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.</strong>
|
|
Nature Genet. 32: 384-392, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002.
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[PubMed: 12368912]
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[Full Text: https://doi.org/10.1038/ng1002]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jiao, Y., Jin, X., Yan, J., Zhang, C., Jiao, F., Li, X., Roe, B. A., Mount, D. B., Gu, W.
|
|
<strong>A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice.</strong>
|
|
Genomics 91: 407-414, 2008.
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|
|
[PubMed: 18343091]
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[Full Text: https://doi.org/10.1016/j.ygeno.2007.12.010]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kahle, K. T., Flores, B., Bharucha-Goebel, D., Zhang, J., Donkervoort, S., Hegde, M., Hussain, G., Duran, D., Liang, B., Sun, D., Bonnemann, C. G., Delpire, E.
|
|
<strong>Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.</strong>
|
|
Sci. Signal. 9: ra77, 2016. Note: Erratum: Sci. Signal 9: er1, 2016.
|
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|
|
[PubMed: 27485015]
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[Full Text: https://doi.org/10.1126/scisignal.aae0546]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., Gamba, G.
|
|
<strong>Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.</strong>
|
|
J. Biol. Chem. 274: 16355-16362, 1999.
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[PubMed: 10347194]
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[Full Text: https://doi.org/10.1074/jbc.274.23.16355]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Mount, D. B.
|
|
<strong>Personal Communication.</strong>
|
|
Nashville, Tenn. 3/28/2000.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Park, J., Flores, B. R., Scherer, K., Kuepper, H., Rossi, M., Rupprich, K., Rautenberg, M., Deininger, N., Weichselbaum, A., Grimm, A., Sturm, M., Grasshoff, U., Delpire, E., Haack, T. B.
|
|
<strong>De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.</strong>
|
|
J. Med. Genet. 57: 283-288, 2020.
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|
|
[PubMed: 31439721]
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[Full Text: https://doi.org/10.1136/jmedgenet-2019-106273]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Salin-Cantegrel, A., Riviere, J.-B., Dupre, N., Charron, F. M., Shekarabi, M., Karemera, L., Gaspar, C., Horst, J., Tekin, M., Deda, G., Krause, A., Lippert, M. M., Willemsen, M. A. A. P., Jarrer, R., Lapointe, J.-Y., Rouleau, G. A.
|
|
<strong>Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.</strong>
|
|
Neurology 69: 1350-1355, 2007.
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|
|
[PubMed: 17893295]
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[Full Text: https://doi.org/10.1212/01.wnl.0000291779.35643.15]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Salin-Cantegrel, A., Riviere, J.-B., Shekarabi, M., Rasheed, S., DaCal, S., Laganiere, J., Gaudet, R., Rochefort, D., Lesca, G., Gaspar, C., Dion, P. A., Lapointe, J.-Y., Rouleau, G. A.
|
|
<strong>Transit defect of potassium-chloride co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.</strong>
|
|
J. Biol. Chem. 286: 28456-28465, 2011.
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|
[PubMed: 21628467]
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[Full Text: https://doi.org/10.1074/jbc.M111.226894]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Salin-Cantegrel, A., Shekarabi, M., Holbert, S., Dion, P., Rochefort, D., Laganiere, J., Dacal, S., Hince, P., Karemera, L., Gaspar, C., Lapointe, J.-Y., Rouleau, G. A.
|
|
<strong>HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.</strong>
|
|
Hum. Molec. Genet. 17: 2703-2711, 2008.
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|
[PubMed: 18566107]
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[Full Text: https://doi.org/10.1093/hmg/ddn172]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Shi, J., Zhao, F., Pang, X., Huang, S., Wang, J., Chang, X., Zhang, J., Liu, Y., Guo, J., Zhang, W.
|
|
<strong>Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy.</strong>
|
|
Neuromusc. Disord. 31: 149-157, 2021.
|
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|
|
[PubMed: 33323309]
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|
|
[Full Text: https://doi.org/10.1016/j.nmd.2020.11.002]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Uyanik, G., Elcioglu, N., Penzien, J., Gross, C., Yilmaz, Y., Olmez, A., Demir, E., Wahl, D., Scheglmann, K., Winner, B., Bogdahn, U., Topaloglu, H., Hehr, U., Winkler, J.
|
|
<strong>Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.</strong>
|
|
Neurology 66: 1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.
|
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|
|
[PubMed: 16606917]
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[Full Text: https://doi.org/10.1212/01.wnl.0000204181.31175.8b]
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Cassandra L. Kniffin - updated : 10/05/2022<br>Cassandra L. Kniffin - updated : 10/11/2011<br>Cassandra L. Kniffin - updated : 7/29/2010<br>Patricia A. Hartz - updated : 6/6/2008<br>Cassandra L. Kniffin - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 7/25/2007<br>Victor A. McKusick - updated : 10/4/2002
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Paul J. Converse : 4/26/2000
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carol : 01/09/2024<br>alopez : 01/08/2024<br>alopez : 10/07/2022<br>ckniffin : 10/05/2022<br>carol : 09/15/2016<br>alopez : 03/16/2016<br>carol : 11/26/2014<br>carol : 9/16/2013<br>terry : 6/6/2012<br>terry : 10/26/2011<br>carol : 10/14/2011<br>terry : 10/12/2011<br>ckniffin : 10/11/2011<br>wwang : 8/5/2010<br>ckniffin : 7/29/2010<br>mgross : 6/11/2008<br>mgross : 6/11/2008<br>terry : 6/6/2008<br>wwang : 4/7/2008<br>ckniffin : 3/31/2008<br>wwang : 8/2/2007<br>ckniffin : 7/25/2007<br>cwells : 11/12/2003<br>alopez : 1/16/2003<br>alopez : 11/7/2002<br>cwells : 10/7/2002<br>terry : 10/4/2002<br>mgross : 4/26/2000
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