3747 lines
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Entry
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- *605775 - KELCH-LIKE 3; KLHL3
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- OMIM
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<p>
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<span class="h4">*605775</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605775">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="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=ENSG00000146021;t=ENST00000309755" 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=26249" 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=605775" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000146021;t=ENST00000309755" 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_001257194,NM_001257195,NM_017415" 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_017415" 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=605775" 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=09011&isoform_id=09011_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/KLHL3" 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/2795825,6644176,6644178,6644293,13431657,21706490,71296962,119582587,119582588,166235129,189054481,221043102,221044806,380692310,380692312,929654264" 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/Q9UH77" 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=26249" 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=ENSG00000146021;t=ENST00000309755" 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=KLHL3" 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=KLHL3" 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+26249" 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/KLHL3" 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:26249" 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/26249" 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=chr5&hgg_gene=ENST00000309755.9&hgg_start=137617500&hgg_end=137736089&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 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/klhl3" 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=605775[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 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=605775[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/ENSG00000146021" 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=KLHL3" 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=KLHL3" 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=KLHL3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KLHL3&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/PA30144" 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:6354" 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/FBgn0001301.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:2445185" 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/KLHL3#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:2445185" 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/26249/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=26249" 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=WBGene00002184;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-120203-4" 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=KLHL3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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605775
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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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KELCH-LIKE 3; KLHL3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KLHL3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KLHL3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/5/493?start=-3&limit=10&highlight=493">5q31.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:137617500-137736089&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'})">5:137,617,500-137,736,089</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</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="1">
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<span class="mim-font">
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<a href="/geneMap/5/493?start=-3&limit=10&highlight=493">
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5q31.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Pseudohypoaldosteronism, type IID
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614495"> 614495 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605775" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605775" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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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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</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="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>KLHL3 belongs to a family of proteins that function as substrate adaptors for cullin-3 (CUL3; <a href="/entry/603136">603136</a>)-dependent E3 ubiquitin ligase complexes. Substrates for KLHL3-CUL3-mediated ubiquitination and degradation include WNK1 (<a href="/entry/605232">605232</a>) and WNK4 (<a href="/entry/601844">601844</a>) (<a href="#5" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24821705" 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 fragment derived from the commonly deleted region in malignant myeloid disorders within 5q31 from a PAC contig, EST database searching, 5-prime RACE, and primers designed for RT-PCR with human bone marrow mRNA as a template, <a href="#3" class="mim-tip-reference" title="Lai, F., Orelli, B. J., Till, B. G., Godley, L. A., Fernald, A. A., Pamintuan, L., Le Beau, M. M. <strong>Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene.</strong> Genomics 66: 65-75, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843806</a>] [<a href="https://doi.org/10.1006/geno.2000.6181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10843806">Lai et al. (2000)</a> cloned a homolog of Drosophila kelch, designated KLHL3, that has a single open reading frame and 3 isoforms with variable first exons. KLHL3a encodes the deduced full-length protein of 587 amino acids, whereas KLHL3b encodes a 555-amino acid protein and KLHL3c encodes a 505-amino acid protein. Instead of generating proteins with unique N-terminal sequences, alternative usage of the promoters affects only the translation initiation site used. <a href="#3" class="mim-tip-reference" title="Lai, F., Orelli, B. J., Till, B. G., Godley, L. A., Fernald, A. A., Pamintuan, L., Le Beau, M. M. <strong>Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene.</strong> Genomics 66: 65-75, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843806</a>] [<a href="https://doi.org/10.1006/geno.2000.6181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10843806">Lai et al. (2000)</a> also identified alternative polyadenylation sites and alternative splicing. The KLHL3 protein shares 77% sequence similarity with Drosophila kelch and 89% similarity with human KLHL2 (<a href="/entry/605774">605774</a>). Like kelch and KLHL2, KLHL3 contains a poxvirus and zinc finger (POZ) domain in the N terminus and 6 tandem repeats (kelch repeats) in the C terminus. Northern blot analysis detected expression of a 6.5-kb mRNA in fetal liver, thymus, and lymph node; the transcript was barely detectable in spleen and appeared to be absent in peripheral blood and bone marrow. Among 50 human tissues examined by dot-blot analysis, cerebellum and pituitary gland gave the strongest signal; all other tissues were positive but at low intensities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10843806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using quantitative RT-PCR, <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> demonstrated that KLHL3 is widely expressed, with the highest level of expression being detected in the cerebellum. Quantitative RT-PCR on segments isolated from mouse cortical nephron showed that Klhl3 is highly expressed in the distal collecting tubule (DCT) and, to a lesser extent, in the connecting tubule. Immunohistochemistry studies on serial mouse kidney sections confirmed that the major site of Klhl3 expression was in the DCT and showed that Klhl3 protein was mainly present on the apical side of the DCT cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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="Lai, F., Orelli, B. J., Till, B. G., Godley, L. A., Fernald, A. A., Pamintuan, L., Le Beau, M. M. <strong>Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene.</strong> Genomics 66: 65-75, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843806</a>] [<a href="https://doi.org/10.1006/geno.2000.6181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10843806">Lai et al. (2000)</a> determined that the KLHL3 gene has 17 exons spanning about 120 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10843806" 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 both HEK 293T cells and mouse distal collecting tubule (mDCT) cells, <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> demonstrated that inhibition of KLHL3 by RNA interference produced an increase in NCC (SLC12A3; <a href="/entry/600968">600968</a>) membrane expression similar to that induced by exposure to a hypotonic low-chloride medium, indicating that KLHL3 inhibits NCC membrane expression. Coimmunoprecipitation studies in HEK 293T cells showed interaction between KLHL3 and NCC, suggesting that KLHL3 might be partially responsible for direct regulation of NCC surface expression. Immunofluorescence experiments in HEK 293T cells showed that hypotonicity decreased the expression of endogenous KLHL3 at the plasma membrane by 30%. These data suggested that decreased KLHL3 expression in the membrane compartment is required to increase NCC surface localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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>WNK4 is an integrative regulator of renal electrolyte transport whose main target is the thiazide-sensitive Na-Cl cotransporter NCC. By injecting constructs encoding human KLHL3, WNK4, and CUL3 and mouse Ncc into Xenopus oocytes, <a href="#6" class="mim-tip-reference" title="Wu, G., Peng, J.-B. <strong>Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.</strong> FEBS Lett. 587: 1717-1722, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665031[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.febslet.2013.04.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665031">Wu and Peng (2013)</a> found that KLHL3 inhibited the positive effect of WNK4 on Ncc by decreasing WNK4 protein abundance via WNK4 ubiquitination and degradation. KLHL3 had no effect on Ncc or on the coexpressed downstream kinase OSR1 (OXSR1; <a href="/entry/604046">604046</a>). <a href="#6" class="mim-tip-reference" title="Wu, G., Peng, J.-B. <strong>Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.</strong> FEBS Lett. 587: 1717-1722, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665031[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.febslet.2013.04.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665031">Wu and Peng (2013)</a> concluded that KLHL3 is an important adaptor for ubiquitination and proteasome-mediated downregulation of WNK4 and regulation of renal Na+ reuptake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23665031" 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>Among 52 PHAII kindreds including 126 affected subjects, <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified both dominant and recessive mutations in the KLHL3 gene resulting in PHA2D (<a href="/entry/614495">614495</a>). Whereas recessive KLHL3 mutations were distributed throughout the encoded protein, dominant KLHL3 mutations showed marked clustering. Nine of 16 dominant mutations altered 1 of the last 4 amino acids of the 6 'd-a' loops that connect the outermost (d) beta-strand of 1 kelch propeller blade to the innermost (a) beta-strand of the next blade. Two others were in 'b-c' loops. These dominant PHAH mutations lay near the hub of the propeller at or near sites implicated in substrate binding in paralogs. Three other dominant mutations clustered within the BTB domain, at or near sites implicated in cullin binding in paralogs. <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> inferred that dominant mutations in KLHL3 probably impair binding either to specific substrates or to CUL3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected individuals from 16 of 45 families with hyperkalemic hypertension, <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified missense mutations in the KLHL3 gene, present in heterozygosity in 12 of the families (see, e.g., <a href="#0003">605775.0003</a>, <a href="#0004">605775.0004</a>, <a href="#0008">605775.0008</a>, <a href="#0010">605775.0010</a>, and <a href="#0011">605775.0011</a>) and in homozygosity in 4 (see, e.g., <a href="#0012">605775.0012</a>). On average, the recessive cases were diagnosed at an earlier age (2.5 months to 17 years) than those with heterozygous mutations (15 to 56 years) and had a more severe phenotype. Screening of the KLHL3 gene in 1,232 individuals with essential hypertension (see <a href="/entry/145000">145000</a>) revealed only 1 deleterious mutation in a hypertensive patient with mild hyperkalemia; <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> concluded that missense mutations causing hyperkalemic hypertension are rare in the general hypertensive population of European descent. In addition, analysis of a total of 794 SNPs spread over 1 Mb of KLHL3 in 69,000 individuals showed no significant association with systolic or diastolic blood pressure or with both traits combined when results were adjusted for age, gender, and body mass index, suggesting that common variation in KLHL3 has no significant impact on blood pressure regulation in healthy populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Wu, G., Peng, J.-B. <strong>Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.</strong> FEBS Lett. 587: 1717-1722, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665031[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.febslet.2013.04.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665031">Wu and Peng (2013)</a> found that wildtype KLHL3 reduced the protein content of epitope-tagged human WNK4 following coexpression in Xenopus oocytes, whereas KLHL3 with any 1 of 5 representative mutations showed higher WNK4 protein content. Wildtype KLHL3 exhibited robust inhibition of Na+ uptake by oocytes coexpressing mouse Ncc. In contrast, all 5 KLHL3 mutants more weakly inhibited Ncc-dependent Na+ uptake in coexpressed oocytes. <a href="#6" class="mim-tip-reference" title="Wu, G., Peng, J.-B. <strong>Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.</strong> FEBS Lett. 587: 1717-1722, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665031[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.febslet.2013.04.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665031">Wu and Peng (2013)</a> concluded that PHA2D-causing mutations in KLHL3 interfere with the role of KLHL3 as an adaptor for ubiquitination and proteasome-mediated downregulation of WNK4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23665031" 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>Exclusion Studies</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Lai, F., Orelli, B. J., Till, B. G., Godley, L. A., Fernald, A. A., Pamintuan, L., Le Beau, M. M. <strong>Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene.</strong> Genomics 66: 65-75, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843806</a>] [<a href="https://doi.org/10.1006/geno.2000.6181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10843806">Lai et al. (2000)</a> detected no inactivating mutations of KLHL3 in malignant myeloid disorders with loss of 5q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10843806" 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 transgenic mice, <a href="#5" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al. (2014)</a> found that heterozygous expression of human KLHL3 with the arg528-to-his (R528H; <a href="#0004">605775.0004</a>) mutation caused a high salt-dependent elevation in systolic blood pressure compared with control mice or KLHL3(R528H/+) mice on a low-salt diet. Transgenic KLHL3(R528H/+) mice also showed hyperkalemia and metabolic acidosis under both low- and high-salt conditions. Homozygous KLHL3(R528H/R528H) mice showed similar salt-sensitive hypertension, hyperkalemia, and metabolic acidosis. KLHL3(R528H/+) mice had elevated renal expression of the kinases Wnk1 (<a href="/entry/605232">605232</a>) and Wnk4 (<a href="/entry/601844">601844</a>) in distal convoluted tubules, resulting in increased phosphorylation of the Wnk targets Osr1 and Spak (STK39; <a href="/entry/607648">607648</a>) and of the sodium-chloride channel Ncc. <a href="#5" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al. (2014)</a> proposed that the R528H mutation interferes with binding of KLHL3 to WNK1 and WNK4, impairing ubiquitination and degradation of the kinases and resulting in activation of a phosphorylation cascade that elevates activity of sodium channels, such as ENaC (see <a href="/entry/600228">600228</a>), and sodium-chloride channels, such as NCC, at the distal convoluted tubule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24821705" 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=605775[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199469644 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469644;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=rs199469644" 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=rs199469644" 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=RCV000128499 OR RCV001610387" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128499, RCV001610387" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128499...</a>
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<p>In all affected members of a family with pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified homozygosity for a G-to-A transition in the KLHL3 gene that resulted in a trp-to-ter substitution at codon 470 (W470X). Affected individuals were sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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">rs199469639 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469639;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=rs199469639" 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=rs199469639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 1 family with pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified compound heterozygosity for missense mutations in the KLHL3 gene, one a T-to-G transversion resulting in a phe-to-cys substitution at codon 322 (F322C). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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>.0003 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT OR RECESSIVE</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> rs199469641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469641;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/rs199469641?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=rs199469641" 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=rs199469641" 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=RCV000023474 OR RCV000128521" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023474, RCV000128521" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023474...</a>
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<p>In 1 family with pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified compound heterozygosity for missense mutations in the KLHL3 gene; one was a C-to-T transition resulting in a ser-to-leu substitution at codon 410 (S410L). See also <a href="#0007">605775.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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 French male proband diagnosed at 29 years of age with hyperkalemic hypertension (PHAII), <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified heterozygosity for the S410L substitution, which occurs at a conserved residue in the KLHL3 gene. The mutation was not found in 800 normotensive controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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">rs199469636 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469636;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=rs199469636" 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=rs199469636" 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=RCV000023475 OR RCV000128519 OR RCV002513190" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023475, RCV000128519, RCV002513190" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023475...</a>
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<p>In 2 families segregating autosomal dominant pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified a G-to-A transition in the KLHL3 gene resulting in an arg-to-his substitution at codon 528 (R528H). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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 French families with hyperkalemic hypertension (PHAII), <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified heterozygosity for a 1583G-A transition in the KLHL3 gene, resulting in the R528H substitution, located at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with N529 (see <a href="#0011">605775.0011</a>). The mutation segregated with disease in each family and was not found in 800 normotensive controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transgenic mice expressing human KLHL3 with the R528H mutation, <a href="#5" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al. (2014)</a> presented evidence that R528H causes PHA2D by interfering with KLHL3-dependent binding and degradation of the kinases WNK1 (<a href="/entry/605232">605232</a>) and WNK4 (<a href="/entry/601844">601844</a>), leading to excessive phosphorylation and activation of sodium channels, such as ENaC (see <a href="/entry/600228">600228</a>), and sodium-chloride channels, such as NCC (SLC12A3; <a href="/entry/600968">600968</a>), in distal convoluted tubules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24821705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL RECESSIVE</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> rs199469638 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469638;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/rs199469638?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=rs199469638" 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=rs199469638" 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=RCV000023476 OR RCV000128514 OR RCV004772832" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023476, RCV000128514, RCV004772832" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023476...</a>
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<p>In 3 affected sibs from a family with autosomal recessive pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified a C-to-T transition resulting in an arg-to-ter substitution at codon 240 (R240X) in compound heterozygosity with a missense mutation (see <a href="#0006">605775.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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> rs199469640 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469640;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/rs199469640?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=rs199469640" 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=rs199469640" 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=RCV000023477 OR RCV000128515" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023477, RCV000128515" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023477...</a>
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<p>In a family with autosomal recessive pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified compound heterozygosity for a G-to-T transversion in the KLHL3 gene resulting in an arg-to-ile substitution at codon 336 (R336I) and a nonsense mutation (see <a href="#0005">605775.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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">rs199469645 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469645;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=rs199469645" 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=rs199469645" 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=RCV000023478 OR RCV000128524 OR RCV003556076" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023478, RCV000128524, RCV003556076" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023478...</a>
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<p>In a single proband with pseudohypoaldosteronism type II (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified compound heterozygosity for the S410L mutation in KLHL3 (<a href="#0003">605775.0003</a>) and an A-to-G transition resulting in a tyr-to-cys substitution at codon 557 (Y557C). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</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">rs199469635 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469635;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=rs199469635" 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=rs199469635" 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=RCV000023479 OR RCV000128518" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023479, RCV000128518" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023479...</a>
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<p>In a family segregating autosomal dominant pseudohypoaldosteronism type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified a C-to-T transition in the KLHL3 gene resulting in an arg-to-cys substitution at codon 528 (R528C). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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 21-year-old Canadian male proband with hyperkalemic hypertension (PHAII), <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified heterozygosity for a 1582C-T transition in the KLHL3 gene, resulting in the R528C substitution, located at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with N529 (see <a href="#0011">605775.0011</a>). The mutation was not found in 800 normotensive controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</strong>
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KLHL3, SER433ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199469632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199469632;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=rs199469632" 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=rs199469632" 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=RCV000023480 OR RCV000128523" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023480, RCV000128523" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023480...</a>
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<p>In 2 independent pedigrees segregating autosomal dominant pseudohypoaldosteronism, type IID (PHA2D; <a href="/entry/614495">614495</a>), <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified heterozygosity for a G-to-A transition in the KLHL3 gene resulting in an ser-to-asn substitution at codon 433 (S433N). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<strong>.0010 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</strong>
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KLHL3, ALA398VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907155 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907155;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=rs387907155" 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=rs387907155" 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=RCV000024252" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024252" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024252</a>
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<p>In affected members of a large 4-generation French family segregating autosomal dominant hyperkalemic hypertension (PHA2D; <a href="/entry/614495">614495</a>), <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified heterozygosity for a 1193C-T transition in the KLHL3 gene, resulting in an ala398-to-val (A398V) substitution at a conserved residue. The mutation was not found in unaffected family members or in 800 normotensive controls. The phenotype was mild in the 14 affected family members, only 3 of whom had hypertension, with a modest but significant increase in serum potassium present in the remaining affected individuals compared to unaffected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</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> rs562736621 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs562736621;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/rs562736621?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=rs562736621" 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=rs562736621" 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=RCV000024253" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024253" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024253</a>
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<p>In a 47-year-old French man with hyperkalemic hypertension (PHA2D; <a href="/entry/614495">614495</a>), <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified heterozygosity for a 1587C-A transversion in the KLHL3 gene, resulting in an asn529-to-lys (N529K) substitution at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with R528 (see <a href="#0004">605775.0004</a> and <a href="#0008">605775.0008</a>) and Y577. The mutation was not found in 800 normotensive controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</strong>
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KLHL3, PRO426LEU
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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> rs387907156 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907156;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/rs387907156?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=rs387907156" 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=rs387907156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024254" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024254" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024254</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 male probands from unrelated consanguineous families with hyperkalemic hypertension (PHA2D; <a href="/entry/614495">614495</a>), <a href="#4" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> identified homozygosity for a 1277C-T transition in the KLHL3 gene, resulting in a pro426-to-leu (P426L) substitution at a conserved residue in the III-IV interblade d-a loop. The mutation was not found in 800 normotensive controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<ol>
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<li>
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<a id="1" class="mim-anchor"></a>
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<a id="Boyden2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others.
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<strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong>
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Nature 482: 98-102, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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=22266938" 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/nature10814" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Gross2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 11/24/2014.
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<a id="3" class="mim-anchor"></a>
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<a id="Lai2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lai, F., Orelli, B. J., Till, B. G., Godley, L. A., Fernald, A. A., Pamintuan, L., Le Beau, M. M.
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<strong>Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene.</strong>
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Genomics 66: 65-75, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843806</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10843806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.2000.6181" target="_blank">Full Text</a>]
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Louis-Dit-Picard2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others.
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<strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong>
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Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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/ng.2218" target="_blank">Full Text</a>]
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Susa2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S.
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<strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong>
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Hum. Molec. Genet. 23: 5052-5060, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24821705" 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/ddu217" target="_blank">Full Text</a>]
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Wu2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, G., Peng, J.-B.
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<strong>Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.</strong>
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FEBS Lett. 587: 1717-1722, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665031[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=23665031" 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.febslet.2013.04.032" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 11/24/2014
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</span>
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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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Patricia A. Hartz - updated : 11/3/2014<br>Patricia A. Hartz - updated : 10/27/2014<br>Marla J. F. O'Neill - updated : 5/14/2012<br>Ada Hamosh - updated : 2/22/2012
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini : 3/26/2001
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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mgross : 11/24/2014
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<span class="mim-text-font">
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mgross : 11/7/2014<br>mgross : 11/7/2014<br>mcolton : 11/3/2014<br>mgross : 10/28/2014<br>mcolton : 10/27/2014<br>terry : 6/11/2012<br>terry : 5/15/2012<br>carol : 5/14/2012<br>alopez : 2/27/2012<br>terry : 2/22/2012<br>carol : 3/26/2001
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605775
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<div>
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<h3>
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<span class="mim-font">
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KELCH-LIKE 3; KLHL3
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KLHL3</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 5q31.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:137,617,500-137,736,089 </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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<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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Location
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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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<td rowspan="1">
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<span class="mim-font">
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5q31.2
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<td>
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<span class="mim-font">
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Pseudohypoaldosteronism, type IID
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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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614495
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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; 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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</tbody>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>KLHL3 belongs to a family of proteins that function as substrate adaptors for cullin-3 (CUL3; 603136)-dependent E3 ubiquitin ligase complexes. Substrates for KLHL3-CUL3-mediated ubiquitination and degradation include WNK1 (605232) and WNK4 (601844) (Susa et al., 2014). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a fragment derived from the commonly deleted region in malignant myeloid disorders within 5q31 from a PAC contig, EST database searching, 5-prime RACE, and primers designed for RT-PCR with human bone marrow mRNA as a template, Lai et al. (2000) cloned a homolog of Drosophila kelch, designated KLHL3, that has a single open reading frame and 3 isoforms with variable first exons. KLHL3a encodes the deduced full-length protein of 587 amino acids, whereas KLHL3b encodes a 555-amino acid protein and KLHL3c encodes a 505-amino acid protein. Instead of generating proteins with unique N-terminal sequences, alternative usage of the promoters affects only the translation initiation site used. Lai et al. (2000) also identified alternative polyadenylation sites and alternative splicing. The KLHL3 protein shares 77% sequence similarity with Drosophila kelch and 89% similarity with human KLHL2 (605774). Like kelch and KLHL2, KLHL3 contains a poxvirus and zinc finger (POZ) domain in the N terminus and 6 tandem repeats (kelch repeats) in the C terminus. Northern blot analysis detected expression of a 6.5-kb mRNA in fetal liver, thymus, and lymph node; the transcript was barely detectable in spleen and appeared to be absent in peripheral blood and bone marrow. Among 50 human tissues examined by dot-blot analysis, cerebellum and pituitary gland gave the strongest signal; all other tissues were positive but at low intensities. </p><p>Using quantitative RT-PCR, Louis-Dit-Picard et al. (2012) demonstrated that KLHL3 is widely expressed, with the highest level of expression being detected in the cerebellum. Quantitative RT-PCR on segments isolated from mouse cortical nephron showed that Klhl3 is highly expressed in the distal collecting tubule (DCT) and, to a lesser extent, in the connecting tubule. Immunohistochemistry studies on serial mouse kidney sections confirmed that the major site of Klhl3 expression was in the DCT and showed that Klhl3 protein was mainly present on the apical side of the DCT cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lai et al. (2000) determined that the KLHL3 gene has 17 exons spanning about 120 kb of genomic DNA. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gross (2014) mapped the KLHL3 gene to chromosome 5q31.2 based on an alignment of the KLHL3 sequence (GenBank AF208068) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In both HEK 293T cells and mouse distal collecting tubule (mDCT) cells, Louis-Dit-Picard et al. (2012) demonstrated that inhibition of KLHL3 by RNA interference produced an increase in NCC (SLC12A3; 600968) membrane expression similar to that induced by exposure to a hypotonic low-chloride medium, indicating that KLHL3 inhibits NCC membrane expression. Coimmunoprecipitation studies in HEK 293T cells showed interaction between KLHL3 and NCC, suggesting that KLHL3 might be partially responsible for direct regulation of NCC surface expression. Immunofluorescence experiments in HEK 293T cells showed that hypotonicity decreased the expression of endogenous KLHL3 at the plasma membrane by 30%. These data suggested that decreased KLHL3 expression in the membrane compartment is required to increase NCC surface localization. </p><p>WNK4 is an integrative regulator of renal electrolyte transport whose main target is the thiazide-sensitive Na-Cl cotransporter NCC. By injecting constructs encoding human KLHL3, WNK4, and CUL3 and mouse Ncc into Xenopus oocytes, Wu and Peng (2013) found that KLHL3 inhibited the positive effect of WNK4 on Ncc by decreasing WNK4 protein abundance via WNK4 ubiquitination and degradation. KLHL3 had no effect on Ncc or on the coexpressed downstream kinase OSR1 (OXSR1; 604046). Wu and Peng (2013) concluded that KLHL3 is an important adaptor for ubiquitination and proteasome-mediated downregulation of WNK4 and regulation of renal Na+ reuptake. </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">
|
|
<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>Among 52 PHAII kindreds including 126 affected subjects, Boyden et al. (2012) identified both dominant and recessive mutations in the KLHL3 gene resulting in PHA2D (614495). Whereas recessive KLHL3 mutations were distributed throughout the encoded protein, dominant KLHL3 mutations showed marked clustering. Nine of 16 dominant mutations altered 1 of the last 4 amino acids of the 6 'd-a' loops that connect the outermost (d) beta-strand of 1 kelch propeller blade to the innermost (a) beta-strand of the next blade. Two others were in 'b-c' loops. These dominant PHAH mutations lay near the hub of the propeller at or near sites implicated in substrate binding in paralogs. Three other dominant mutations clustered within the BTB domain, at or near sites implicated in cullin binding in paralogs. Boyden et al. (2012) inferred that dominant mutations in KLHL3 probably impair binding either to specific substrates or to CUL3. </p><p>In affected individuals from 16 of 45 families with hyperkalemic hypertension, Louis-Dit-Picard et al. (2012) identified missense mutations in the KLHL3 gene, present in heterozygosity in 12 of the families (see, e.g., 605775.0003, 605775.0004, 605775.0008, 605775.0010, and 605775.0011) and in homozygosity in 4 (see, e.g., 605775.0012). On average, the recessive cases were diagnosed at an earlier age (2.5 months to 17 years) than those with heterozygous mutations (15 to 56 years) and had a more severe phenotype. Screening of the KLHL3 gene in 1,232 individuals with essential hypertension (see 145000) revealed only 1 deleterious mutation in a hypertensive patient with mild hyperkalemia; Louis-Dit-Picard et al. (2012) concluded that missense mutations causing hyperkalemic hypertension are rare in the general hypertensive population of European descent. In addition, analysis of a total of 794 SNPs spread over 1 Mb of KLHL3 in 69,000 individuals showed no significant association with systolic or diastolic blood pressure or with both traits combined when results were adjusted for age, gender, and body mass index, suggesting that common variation in KLHL3 has no significant impact on blood pressure regulation in healthy populations. </p><p>Wu and Peng (2013) found that wildtype KLHL3 reduced the protein content of epitope-tagged human WNK4 following coexpression in Xenopus oocytes, whereas KLHL3 with any 1 of 5 representative mutations showed higher WNK4 protein content. Wildtype KLHL3 exhibited robust inhibition of Na+ uptake by oocytes coexpressing mouse Ncc. In contrast, all 5 KLHL3 mutants more weakly inhibited Ncc-dependent Na+ uptake in coexpressed oocytes. Wu and Peng (2013) concluded that PHA2D-causing mutations in KLHL3 interfere with the role of KLHL3 as an adaptor for ubiquitination and proteasome-mediated downregulation of WNK4. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
|
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Lai et al. (2000) detected no inactivating mutations of KLHL3 in malignant myeloid disorders with loss of 5q. </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">
|
|
<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>Using transgenic mice, Susa et al. (2014) found that heterozygous expression of human KLHL3 with the arg528-to-his (R528H; 605775.0004) mutation caused a high salt-dependent elevation in systolic blood pressure compared with control mice or KLHL3(R528H/+) mice on a low-salt diet. Transgenic KLHL3(R528H/+) mice also showed hyperkalemia and metabolic acidosis under both low- and high-salt conditions. Homozygous KLHL3(R528H/R528H) mice showed similar salt-sensitive hypertension, hyperkalemia, and metabolic acidosis. KLHL3(R528H/+) mice had elevated renal expression of the kinases Wnk1 (605232) and Wnk4 (601844) in distal convoluted tubules, resulting in increased phosphorylation of the Wnk targets Osr1 and Spak (STK39; 607648) and of the sodium-chloride channel Ncc. Susa et al. (2014) proposed that the R528H mutation interferes with binding of KLHL3 to WNK1 and WNK4, impairing ubiquitination and degradation of the kinases and resulting in activation of a phosphorylation cascade that elevates activity of sodium channels, such as ENaC (see 600228), and sodium-chloride channels, such as NCC, at the distal convoluted tubule. </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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
|
<strong>12 Selected Examples):</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL RECESSIVE</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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|
|
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KLHL3, TRP470TER
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<br />
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|
|
SNP: rs199469644,
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|
|
ClinVar: RCV000128499, RCV001610387
|
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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 all affected members of a family with pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified homozygosity for a G-to-A transition in the KLHL3 gene that resulted in a trp-to-ter substitution at codon 470 (W470X). Affected individuals were sibs. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, PHE322CYS
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs199469639,
|
|
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|
|
|
|
|
ClinVar: RCV000023473, RCV000128507
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 family with pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified compound heterozygosity for missense mutations in the KLHL3 gene, one a T-to-G transversion resulting in a phe-to-cys substitution at codon 322 (F322C). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT OR RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, SER410LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199469641,
|
|
|
|
|
|
gnomAD: rs199469641,
|
|
|
|
|
|
ClinVar: RCV000023474, RCV000128521
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 family with pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified compound heterozygosity for missense mutations in the KLHL3 gene; one was a C-to-T transition resulting in a ser-to-leu substitution at codon 410 (S410L). See also 605775.0007. </p><p>In a French male proband diagnosed at 29 years of age with hyperkalemic hypertension (PHAII), Louis-Dit-Picard et al. (2012) identified heterozygosity for the S410L substitution, which occurs at a conserved residue in the KLHL3 gene. The mutation was not found in 800 normotensive controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, ARG528HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199469636,
|
|
|
|
|
|
|
|
ClinVar: RCV000023475, RCV000128519, RCV002513190
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families segregating autosomal dominant pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified a G-to-A transition in the KLHL3 gene resulting in an arg-to-his substitution at codon 528 (R528H). </p><p>In 3 French families with hyperkalemic hypertension (PHAII), Louis-Dit-Picard et al. (2012) identified heterozygosity for a 1583G-A transition in the KLHL3 gene, resulting in the R528H substitution, located at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with N529 (see 605775.0011). The mutation segregated with disease in each family and was not found in 800 normotensive controls. </p><p>Using transgenic mice expressing human KLHL3 with the R528H mutation, Susa et al. (2014) presented evidence that R528H causes PHA2D by interfering with KLHL3-dependent binding and degradation of the kinases WNK1 (605232) and WNK4 (601844), leading to excessive phosphorylation and activation of sodium channels, such as ENaC (see 600228), and sodium-chloride channels, such as NCC (SLC12A3; 600968), in distal convoluted tubules. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, ARG240TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199469638,
|
|
|
|
|
|
gnomAD: rs199469638,
|
|
|
|
|
|
ClinVar: RCV000023476, RCV000128514, RCV004772832
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected sibs from a family with autosomal recessive pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified a C-to-T transition resulting in an arg-to-ter substitution at codon 240 (R240X) in compound heterozygosity with a missense mutation (see 605775.0006). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, ARG336ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199469640,
|
|
|
|
|
|
gnomAD: rs199469640,
|
|
|
|
|
|
ClinVar: RCV000023477, RCV000128515
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with autosomal recessive pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified compound heterozygosity for a G-to-T transversion in the KLHL3 gene resulting in an arg-to-ile substitution at codon 336 (R336I) and a nonsense mutation (see 605775.0005). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, TYR557CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199469645,
|
|
|
|
|
|
|
|
ClinVar: RCV000023478, RCV000128524, RCV003556076
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a single proband with pseudohypoaldosteronism type II (PHA2D; 614495), Boyden et al. (2012) identified compound heterozygosity for the S410L mutation in KLHL3 (605775.0003) and an A-to-G transition resulting in a tyr-to-cys substitution at codon 557 (Y557C). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KLHL3, ARG528CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199469635,
|
|
|
|
|
|
|
|
ClinVar: RCV000023479, RCV000128518
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family segregating autosomal dominant pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified a C-to-T transition in the KLHL3 gene resulting in an arg-to-cys substitution at codon 528 (R528C). </p><p>In a 21-year-old Canadian male proband with hyperkalemic hypertension (PHAII), Louis-Dit-Picard et al. (2012) identified heterozygosity for a 1582C-T transition in the KLHL3 gene, resulting in the R528C substitution, located at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with N529 (see 605775.0011). The mutation was not found in 800 normotensive controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</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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KLHL3, SER433ASN
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<br />
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SNP: rs199469632,
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ClinVar: RCV000023480, RCV000128523
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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 independent pedigrees segregating autosomal dominant pseudohypoaldosteronism, type IID (PHA2D; 614495), Boyden et al. (2012) identified heterozygosity for a G-to-A transition in the KLHL3 gene resulting in an ser-to-asn substitution at codon 433 (S433N). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</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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KLHL3, ALA398VAL
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<br />
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SNP: rs387907155,
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ClinVar: RCV000024252
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large 4-generation French family segregating autosomal dominant hyperkalemic hypertension (PHA2D; 614495), Louis-Dit-Picard et al. (2012) identified heterozygosity for a 1193C-T transition in the KLHL3 gene, resulting in an ala398-to-val (A398V) substitution at a conserved residue. The mutation was not found in unaffected family members or in 800 normotensive controls. The phenotype was mild in the 14 affected family members, only 3 of whom had hypertension, with a modest but significant increase in serum potassium present in the remaining affected individuals compared to unaffected family members. </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 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</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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KLHL3, ASN529LYS
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<br />
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SNP: rs562736621,
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gnomAD: rs562736621,
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ClinVar: RCV000024253
|
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|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 47-year-old French man with hyperkalemic hypertension (PHA2D; 614495), Louis-Dit-Picard et al. (2012) identified heterozygosity for a 1587C-A transversion in the KLHL3 gene, resulting in an asn529-to-lys (N529K) substitution at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with R528 (see 605775.0004 and 605775.0008) and Y577. The mutation was not found in 800 normotensive controls. </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>.0012 PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT</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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KLHL3, PRO426LEU
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<br />
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SNP: rs387907156,
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gnomAD: rs387907156,
|
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ClinVar: RCV000024254
|
|
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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 male probands from unrelated consanguineous families with hyperkalemic hypertension (PHA2D; 614495), Louis-Dit-Picard et al. (2012) identified homozygosity for a 1277C-T transition in the KLHL3 gene, resulting in a pro426-to-leu (P426L) substitution at a conserved residue in the III-IV interblade d-a loop. The mutation was not found in 800 normotensive controls. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</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>
|
|
<p class="mim-text-font">
|
|
Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others.
|
|
<strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong>
|
|
Nature 482: 98-102, 2012.
|
|
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|
|
[PubMed: 22266938]
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|
|
[Full Text: https://doi.org/10.1038/nature10814]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Gross, M. B.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 11/24/2014.
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|
|
|
</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Lai, F., Orelli, B. J., Till, B. G., Godley, L. A., Fernald, A. A., Pamintuan, L., Le Beau, M. M.
|
|
<strong>Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene.</strong>
|
|
Genomics 66: 65-75, 2000.
|
|
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|
|
|
[PubMed: 10843806]
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|
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|
|
[Full Text: https://doi.org/10.1006/geno.2000.6181]
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</p>
|
|
</li>
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others.
|
|
<strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong>
|
|
Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.
|
|
|
|
|
|
[PubMed: 22406640]
|
|
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|
|
[Full Text: https://doi.org/10.1038/ng.2218]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S.
|
|
<strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong>
|
|
Hum. Molec. Genet. 23: 5052-5060, 2014.
|
|
|
|
|
|
[PubMed: 24821705]
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|
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[Full Text: https://doi.org/10.1093/hmg/ddu217]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Wu, G., Peng, J.-B.
|
|
<strong>Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.</strong>
|
|
FEBS Lett. 587: 1717-1722, 2013.
|
|
|
|
|
|
[PubMed: 23665031]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.febslet.2013.04.032]
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</p>
|
|
</li>
|
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</ol>
|
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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|
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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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Matthew B. Gross - updated : 11/24/2014<br>Patricia A. Hartz - updated : 11/3/2014<br>Patricia A. Hartz - updated : 10/27/2014<br>Marla J. F. O'Neill - updated : 5/14/2012<br>Ada Hamosh - updated : 2/22/2012
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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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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini : 3/26/2001
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mgross : 11/24/2014<br>mgross : 11/7/2014<br>mgross : 11/7/2014<br>mcolton : 11/3/2014<br>mgross : 10/28/2014<br>mcolton : 10/27/2014<br>terry : 6/11/2012<br>terry : 5/15/2012<br>carol : 5/14/2012<br>alopez : 2/27/2012<br>terry : 2/22/2012<br>carol : 3/26/2001
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