3460 lines
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Entry
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- *601844 - PROTEIN KINASE, LYSINE-DEFICIENT 4; WNK4
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601844</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601844">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000126562;t=ENST00000246914" 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=65266" 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=601844" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000126562;t=ENST00000246914" 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_001321299,NM_032387,XM_017024962,XM_017024966,XM_047436554,XM_047436556,XM_047436557,XM_047436558,XM_047436559,XM_047436560,XM_047436561,XM_047436562,XM_047436563" 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_032387" 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=601844" 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=03505&isoform_id=03505_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/WNK4" 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/13161938,15131540,15212448,21755379,21755447,34365793,41688789,119581285,119581286,166706823,194378026,223460150,1007892890,1034600905,1034600914,2217313326,2217313328,2217313330,2217313332,2217313334,2217313336,2217313338,2217313340,2217313342,2462557042,2462557044,2462557046,2462557048,2462557050,2462557052,2462557054,2462557056,2462557058,2462557060,2462557062" 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/Q96J92" 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=65266" 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=ENSG00000126562;t=ENST00000246914" 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=WNK4" 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=WNK4" 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+65266" 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/WNK4" 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:65266" 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/65266" 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=chr17&hgg_gene=ENST00000246914.10&hgg_start=42780610&hgg_end=42797066&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/wnk4" 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=601844[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601844[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/ENSG00000126562" 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=WNK4" 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=WNK4" 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=WNK4" 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=WNK4&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/PA134875400" 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:14544" 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/FBgn0037098.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:1917097" 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/WNK4#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:1917097" 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/65266/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001759/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=65266" 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=WBGene00006941;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-110606-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:65266" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=WNK4&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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601844
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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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PROTEIN KINASE, LYSINE-DEFICIENT 4; WNK4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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PRKWNK4
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=WNK4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">WNK4</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/17/592?start=-3&limit=10&highlight=592">17q21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:42780610-42797066&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'})">17:42,780,610-42,797,066</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">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/592?start=-3&limit=10&highlight=592">
|
|
17q21.2
|
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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">
|
|
Pseudohypoaldosteronism, type IIB
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614491"> 614491 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</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">
|
|
<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>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601844" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601844" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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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|
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<span class="mim-font">
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<p>WNK4 is an integrative regulator of renal electrolyte transport whose main target is the thiazide-sensitive Na-Cl cotransporter NCC (SLC12A3; <a href="/entry/600968">600968</a>) (<a href="#15" 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>). <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>WNK4 is a serine-threonine protein kinase identified by <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> because of its homology to WNK1 (<a href="/entry/605232">605232</a>). Proteins encoded by WNK paralogs show high conservation in the kinase domain and have the distinctive substitution of cysteine for lysine in the active site. The encoded amino acid sequence of WNK4 showed 76% identity to WNK1 across a 370-amino acid segment spanning the kinase domain and the first putative coil domain, 51% identity across an 83-amino acid segment encompassing the C-terminal putative coil domain, and 52% identity across a 102-amino acid segment from residues 604 to 741 of WNK4. The intron-exon boundaries within these domains are conserved between the 2 genes. WNK4 is expressed virtually exclusively in the kidney, where it localizes to the distal convoluted tubule and the cortical collecting duct, adjacent segments of the distal nephron that play a key role in salt, water, potassium, and pH homeostasis. WNK4 is present exclusively in intracellular junctions in the distal convoluted tubule and in both the cytoplasm and intercellular junctions in the cortical collecting duct. WNK4 colocalizes with ZO1 (TJP1; <a href="/entry/601009">601009</a>), a tight junction protein, but not with vinculin (<a href="/entry/193065">193065</a>), an adherens junction protein. Thus, <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> concluded that WNK4 is part of the tight junction complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunohistochemical analysis, <a href="#11" class="mim-tip-reference" title="Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., Volkman, H. M., Wilson, F. H., Hebert, S. C., Lifton, R. P. <strong>WNK4 regulates activity of the epithelial Na(+) channel in vitro and in vivo.</strong> Proc. Nat. Acad. Sci. 104: 4020-4024, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360470[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611727104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360470">Ring et al. (2007)</a> showed Wnk4 expression in mouse distal colon and distal nephron. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The clinical features of type II pseudohypoaldosteronism (PHAII; see <a href="/entry/145260">145260</a>), i.e., hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis, all depend on chloride anion. Furthermore, the observation that pseudohypoaldosteronism phenotypes resulting from WNK mutations constitute a 'mirror image' of the phenotypes resulting from loss-of-function mutations in NCC suggests that PHAII may result from increased SLC12A3 activity due to altered WNK signaling. By studies with heterologous expression of wildtype and mutant mouse Wnk4 in Xenopus oocytes, <a href="#14" class="mim-tip-reference" title="Wilson, F. H., Kahle, K. T., Sabath, E., Lalioti, M. D., Rapson, A. K., Hoover, R. S., Hebert, S. C., Gamba, G., Lifton, R. P. <strong>Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.</strong> Proc. Nat. Acad. Sci. 100: 680-684, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12515852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12515852</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12515852[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.242735399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12515852">Wilson et al. (2003)</a> demonstrated that Slc12a3 activity was inhibited by wildtype but not by mutant Wnk4. Wildtype Wnk4 inhibited Slc12a3 by reducing its expression on the membrane. Inhibition depended on Wnk4 kinase activity, because missense mutations that abrogated kinase function prevented the inhibition. PHAII-causing missense mutations further from the kinase domain also prevented the inhibition of Slc12a3 activity. <a href="#14" class="mim-tip-reference" title="Wilson, F. H., Kahle, K. T., Sabath, E., Lalioti, M. D., Rapson, A. K., Hoover, R. S., Hebert, S. C., Gamba, G., Lifton, R. P. <strong>Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.</strong> Proc. Nat. Acad. Sci. 100: 680-684, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12515852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12515852</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12515852[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.242735399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12515852">Wilson et al. (2003)</a> concluded that WNK4 negatively regulates the surface expression of SLC12A3, and the loss of this regulation may cause an inherited form of hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12515852" 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>Independently, <a href="#16" class="mim-tip-reference" title="Yang, C.-L., Angell, J., Mitchell, R., Ellison, D. H. <strong>WNK kinases regulate thiazide-sensitive Na-Cl cotransport.</strong> J. Clin. Invest. 111: 1039-1045, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12671053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12671053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12671053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI17443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12671053">Yang et al. (2003)</a> found that mouse Wnk4 reduced the plasma membrane association of Slc12a3 in injected Xenopus oocytes. However, they found that some Wnk4 mutations that cause PHAII retained the ability to inhibit Slc12a3. In addition, <a href="#16" class="mim-tip-reference" title="Yang, C.-L., Angell, J., Mitchell, R., Ellison, D. H. <strong>WNK kinases regulate thiazide-sensitive Na-Cl cotransport.</strong> J. Clin. Invest. 111: 1039-1045, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12671053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12671053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12671053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI17443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12671053">Yang et al. (2003)</a> showed that Wnk1 (<a href="/entry/605232">605232</a>) did not affect Slc12a3-mediated sodium uptake in oocytes, but coexpression of Wnk1 with both Wnk4 and Slc12a3 restored sodium uptake to levels observed in oocytes expressing Slc12a3 alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12671053" 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>To investigate the mechanisms by which WNK1 and WNK4 interact to regulate ion transport, <a href="#19" class="mim-tip-reference" title="Yang, C.-L., Zhu, X., Wang, Z., Subramanya, A. R., Ellison, D. H. <strong>Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.</strong> J. Clin. Invest. 115: 1379-1387, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15841204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15841204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15841204[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI22452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15841204">Yang et al. (2005)</a> performed experiments in HEK293 cells and Xenopus oocytes which showed that the WNK4 carboxyl terminus mediates SLC12A3 suppression, that the WNK1 kinase domain interacts with the WNK4 kinase domain, and that WNK1 inhibition of WNK4 is dependent on WNK1 catalytic activity and an intact WNK1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15841204" 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 key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning as reported by <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> implicated the serine-threonine kinase WNK4 in this process. Wildtype WNK4 inhibits SLC12A3, the renal Na-Cl cotransporter (NCC); WNK4 mutations that cause type IIB pseudohypoaldosteronism relieve this inhibition. This explains the hypertension of that disorder but does not account for the hyperkalemia. By expression in Xenopus oocytes, <a href="#4" class="mim-tip-reference" title="Kahle, K. T., Wilson, F. H., Leng, Q., Lalioti, M. D., O'Connell, A. D., Dong, K., Rapson, A. K., MacGregor, G. G., Giebisch, G., Hebert, S. C., Lifton, R. P. <strong>WNK4 regulates the balance between renal NaCl reabsorption and K(+) secretion.</strong> Nature Genet. 35: 372-376, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14608358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14608358</a>] [<a href="https://doi.org/10.1038/ng1271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14608358">Kahle et al. (2003)</a> showed that WNK4 also inhibits the renal K+ channel ROMK (KCNJ1; <a href="/entry/600359">600359</a>). This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of SLC12A3. Notably, the same mutations in WNK4 that relieve SLC12A3 inhibition markedly increase inhibition of ROMK. These findings established WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explained the pathophysiology of PHAII. The findings also identified WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14608358+11498583" 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="#3" class="mim-tip-reference" title="Kahle, K. T., MacGregor, G. G., Wilson, F. H., Van Hoek, A. N., Brown, D., Ardito, T., Kashgarian, M., Giebisch, G., Hebert, S. C., Boulpaep, E. L., Lifton, R. P. <strong>Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.</strong> Proc. Nat. Acad. Sci. 101: 14877-14882, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15465913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15465913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15465913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0406172101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15465913">Kahle et al. (2004)</a> determined that induction of wildtype mammalian Wnk4 reduced transepithelial resistance by increasing the absolute chloride permeability of preformed tight junctions. Wnk4 with a mutation in a residue critical for kinase activity had no effect. Wnk4 did not alter the flux of uncharged solutes, the expression or localization of tight junction proteins, or tight junction structure. <a href="#3" class="mim-tip-reference" title="Kahle, K. T., MacGregor, G. G., Wilson, F. H., Van Hoek, A. N., Brown, D., Ardito, T., Kashgarian, M., Giebisch, G., Hebert, S. C., Boulpaep, E. L., Lifton, R. P. <strong>Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.</strong> Proc. Nat. Acad. Sci. 101: 14877-14882, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15465913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15465913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15465913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0406172101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15465913">Kahle et al. (2004)</a> concluded that WNK4 coordinates tight junction permeability as well as transcellular ion flux to achieve NaCl and K+ homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15465913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coexpression in Xenopus oocytes, <a href="#11" class="mim-tip-reference" title="Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., Volkman, H. M., Wilson, F. H., Hebert, S. C., Lifton, R. P. <strong>WNK4 regulates activity of the epithelial Na(+) channel in vitro and in vivo.</strong> Proc. Nat. Acad. Sci. 104: 4020-4024, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360470[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611727104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360470">Ring et al. (2007)</a> found that mouse Wnk4 inhibited the epithelial Na(+) channel (ENaC), the major mediator of aldosterone-sensitive Na(+) absorption, and that inhibition was independent of Wnk4 kinase activity. Inhibition required intact C termini in ENaC beta (SCNN1B; <a href="/entry/600760">600760</a>)- and gamma (SCNN1G; <a href="/entry/600761">600761</a>)-subunits, which contain PY motifs used to target ENaC for clearance from the plasma membrane. PHAII-causing mutations eliminated the ability of Wnk4 to inhibit ENaC. The colonic epithelium of mice harboring PHAII-mutant Wnk4 showed increased amiloride-sensitive Na(+) flux compared with wildtype littermates. <a href="#11" class="mim-tip-reference" title="Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., Volkman, H. M., Wilson, F. H., Hebert, S. C., Lifton, R. P. <strong>WNK4 regulates activity of the epithelial Na(+) channel in vitro and in vivo.</strong> Proc. Nat. Acad. Sci. 104: 4020-4024, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360470[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611727104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360470">Ring et al. (2007)</a> concluded that ENaC is a downstream WNK4 target and that WNK4 regulates colonic Na(+) absorption. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360470" 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="#12" class="mim-tip-reference" title="Ring, A. M., Leng, Q., Rinehart, J., Wilson, F. H., Kahle, K. T., Hebert, S. C., Lifton, R. P. <strong>An SGK1 site in WNK4 regulates Na(+) channel and K(+) channel activity and has implications for aldosterone signaling and K(+) homeostasis.</strong> Proc. Nat. Acad. Sci. 104: 4025-4029, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360471[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611728104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360471">Ring et al. (2007)</a> showed that mouse Wnk4 is phosphorylated by Sgk1 (<a href="/entry/602958">602958</a>), a mediator of aldosterone signaling, at a site C-terminal to the second coiled-coil domain. A Wnk4 mutant that mimics phosphorylation at the Sgk1 site alleviated inhibition of both ENaC and ROMK channels, resulting in increased K(+) secretion. <a href="#12" class="mim-tip-reference" title="Ring, A. M., Leng, Q., Rinehart, J., Wilson, F. H., Kahle, K. T., Hebert, S. C., Lifton, R. P. <strong>An SGK1 site in WNK4 regulates Na(+) channel and K(+) channel activity and has implications for aldosterone signaling and K(+) homeostasis.</strong> Proc. Nat. Acad. Sci. 104: 4025-4029, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360471[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611728104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360471">Ring et al. (2007)</a> concluded that WNK4 has a role in mediating the aldosterone response to hyperkalemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Yang, C.-L., Zhu, X., Ellison, D. H. <strong>The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.</strong> J. Clin. Invest. 117: 3403-3411, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17975670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17975670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17975670[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI32033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17975670">Yang et al. (2007)</a> noted that WNK1, WNK4, and the kidney-specific WNK1 isoform interact to regulate SLC12A3 activity, suggesting that WNKs form a signaling complex. They found that human WNK3 (<a href="/entry/300358">300358</a>), which is expressed by distal tubule cells, interacted with rodent Wnk1 and Wnk4 to regulate SLC12A3 in cultured kidney cells and Xenopus oocytes. Regulation of SLC12A3 in oocytes resulted from antagonism between WNK3 and Wnk4. A PHAII-associated mutation in Wnk4 exerted a dominant-negative effect on wildtype Wnk4 that mimicked WNK3 excess. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17975670" 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="#2" class="mim-tip-reference" title="He, G., Wang, H.-R., Huang, S.-K., Huang, C.-L. <strong>Intersectin links WNK kinases to endocytosis of ROMK1.</strong> J. Clin. Invest. 117: 1078-1087, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17380208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17380208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17380208[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI30087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17380208">He et al. (2007)</a> showed that mammalian Wnk1 and Wnk4 interacted with the endocytic scaffold protein intersectin-1 (ITSN1; <a href="/entry/602442">602442</a>) and that these interactions were crucial for stimulation of Romk1 endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4 required their proline-rich motifs, but it did not require their kinase activities. PHAII-causing mutations in Wnk4 enhanced the interactions of Wnk4 with Itsn1 and Romk1, leading to increased endocytosis of Romk1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17380208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Yang, C.-L., Liu, X., Paliege, A., Zhu, X., Bachmann, S., Dawson, D. C., Ellison, D. H. <strong>WNK1 and WNK4 modulate CFTR activity.</strong> Biochem. Biophys. Res. Commun. 353: 535-540, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17194447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17194447</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.11.151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17194447">Yang et al. (2007)</a> showed that coexpression of rodent Wnk1 and Wnk4 with human CFTR (<a href="/entry/602421">602421</a>) suppressed CFTR-dependent chloride channel activity in Xenopus oocytes. The effect of Wnk4 was dose dependent, independent of Wnk4 kinase activity, and occurred, at least in part, by reducing CFTR protein abundance at the plasma membrane. In contrast, the effect of Wnk1 on CFTR activity required Wnk1 kinase activity. Moreover, Wnk1 and Wnk4 exhibited additive CFTR inhibition. Mouse Wnk4 with a PHAII-associated mutation was a more potent inhibitor of CFTR activity than wildtype Wnk4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17194447" 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 rodent models of salt-induced hypertension and cultured mouse distal collecting tubule cells, <a href="#9" class="mim-tip-reference" title="Mu, S. Y., Shimosawa, T., Ogura, S., Wang, H., Uetake, Y., Kawakami-Mori, F., Marumo, T., Yatomi, Y., Geller, D. S., Tanaka, H., Fujita, T. <strong>Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension.</strong> Nature Med. 17: 573-580, 2011. Note: Erratum: Nature Med. 17: 1020 only, 2011. Erratum: Nature Med. 18: 630 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499270</a>] [<a href="https://doi.org/10.1038/nm.2337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499270">Mu et al. (2011)</a> found that beta-2 adrenergic receptor (ADRB2; <a href="/entry/109690">109690</a>) stimulation led to decreased transcription of Wnk4. Adrb2 stimulation resulted in cyclic AMP-dependent inhibition of histone deacetylase-8 (HDAC8; <a href="/entry/300269">300269</a>), which permitted increased occupancy of the Wnk4 promoter region by acetylated histones H3 and H4 and the binding of glucocorticoid receptor (GCCR; <a href="/entry/138040">138040</a>) to negative glucocorticoid-responsive elements in the Wnk4 promoter. Downregulation of Wnk4 caused Ncc and ENaC activation, sodium retention, and salt-induced hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21499270" 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>KLHL3 (<a href="/entry/605775">605775</a>) and CUL3 (<a href="/entry/603136">603136</a>) are part of a cullin-RING ubiquitin E3 ligase complex that targets renal electrolyte transporters or their regulators. By injecting constructs encoding human KLHL3, WNK4, and CUL3 and mouse Ncc into Xenopus oocytes, <a href="#15" 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="#15" 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. <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><a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> determined that the WNK4 gene comprises 19 exons contained within 16 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> localized the WNK4 gene to the interval on chromosome 17 between loci D17S250 and D17S579, both of which lie within the minimum genetic interval containing the PHA2B (<a href="/entry/614491">614491</a>) locus on chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> identified 4 missense mutations in the WNK4 gene (<a href="#0001">601844.0001</a>-<a href="#0004">601844.0004</a>) in patients with pseudohypoaldosteronism type IIB (PHA2B). Three of these are charge-changing substitutions that cluster in a span of 4 amino acids just distal to the first putative coil domain, within a negatively charged 10-amino acid segment that is highly conserved among all members of the WNK family in human as well as orthologs in mouse and rat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The causes of hypertension have been obscure owing to the physiologic complexity of the trait. Investigation of mendelian forms of high and low blood pressure has implicated variation in renal salt handling in the pathogenesis of hypertension in humans. Pseudohypoaldosteronism type II (see <a href="/entry/145260">145260</a>) can be caused by mutations in WNK1 or WNK4. Renal expression of both genes is confined to epithelia of the distal nephron--the distal convoluted tubule (DCT), the connecting tubule (CNT), and collecting duct. These observations suggested and in vitro studies supported the idea that the Wnks might regulate Na+, Cl-, and K+ flux pathways in these nephron segments. <a href="#5" class="mim-tip-reference" title="Lalioti, M. D., Zhang, J., Volkman, H. M., Kahle, K. T., Hoffmann, K. E., Toka, H. R., Nelson-Williams, C., Ellison, D. H., Flavell, R., Booth, C. J., Lu, Y., Geller, D. S., Lifton, R. P. <strong>Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.</strong> Nature Genet. 38: 1124-1132, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964266</a>] [<a href="https://doi.org/10.1038/ng1877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964266">Lalioti et al. (2006)</a> showed that renal physiology in mice transgenic for genomic segments harboring wildtype or PHAII mutant Wnk4 is changed in opposite directions: the mice with the PHAII genomic segment had higher blood pressure, hyperkalemia, hypercalciuria, and marked hyperplasia of the DCT, whereas the opposite was true in transgenic mice with the wildtype genomic segment. Genetic deficiency of the Na-Cl cotransporter (NCC) of the DCT reversed phenotypes seen in the mice carrying the PHAII genomic segment, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings established that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Ohta, A., Rai, T., Yui, N., Chiga, M., Yang, S.-S., Lin, S.-H., Sohara, E., Sasaki, S., Uchida, S. <strong>Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.</strong> Hum. Molec. Genet. 18: 3978-3986, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633012</a>] [<a href="https://doi.org/10.1093/hmg/ddp344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633012">Ohta et al. (2009)</a> generated Wnk4-hypomorphic mice by deleting exon 7 of the Wnk4 gene. These mice did not show hypokalemia and metabolic alkalosis but did exhibit low blood pressure and increased sodium and potassium excretion under low-salt diet. Phosphorylation of Osr1 (OXSR1; <a href="/entry/604046">604046</a>)/Spak (STK39; <a href="/entry/607648">607648</a>) and Ncc was significantly reduced in the mutant mice as compared with their wildtype littermates. Protein levels of Romk and maxi-K (KCNMA1; <a href="/entry/600150">600150</a>) were not changed, but the epithelial sodium channel (ENaC) appeared to be activated as a compensatory mechanism for the reduced Ncc function. <a href="#10" class="mim-tip-reference" title="Ohta, A., Rai, T., Yui, N., Chiga, M., Yang, S.-S., Lin, S.-H., Sohara, E., Sasaki, S., Uchida, S. <strong>Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.</strong> Hum. Molec. Genet. 18: 3978-3986, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633012</a>] [<a href="https://doi.org/10.1093/hmg/ddp344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633012">Ohta et al. (2009)</a> concluded that wildtype WNK4 is a positive regulator for the WNK-OSR1/SPAK-NCC cascade and is a potential target of antihypertensive drugs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19633012" 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">rs137853092 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853092;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=rs137853092" 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=rs137853092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with autosomal dominant pseudohypoaldosteronism type IIB (PHA2B; <a href="/entry/614491">614491</a>) previously described by <a href="#1" class="mim-tip-reference" title="Farfel, Z., Iaina, A., Rosenthal, T., Waks, U., Shibolet, S., Gafni, J. <strong>Familial hyperpotassemia and hypertension accompanied by normal plasma aldosterone levels: possible hereditary cell membrane defect.</strong> Arch. Intern. Med. 138: 1828-1832, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/718348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">718348</a>]" pmid="718348">Farfel et al. (1978)</a> and further characterized by <a href="#6" class="mim-tip-reference" title="Mansfield, T. A., Simon, D. B., Farfel, Z., Bia, M., Tucci, J. R., Lebel, M., Gutkin, M., Vialettes, B., Christofilis, M. A., Kauppinen-Makelin, R., Mayan, H., Risch, N., Lifton, R. P. <strong>Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.</strong> Nature Genet. 16: 202-205, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171836</a>] [<a href="https://doi.org/10.1038/ng0697-202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171836">Mansfield et al. (1997)</a>, <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> identified a C-to-G substitution in the WNK4 gene resulting in a glutamine-to-glutamic acid substitution at codon 565 (Q565E), within a highly conserved negatively charged 10-amino acid segment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=718348+9171836+11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Mayan, H., Munter, G., Shaharabany, M., Mouallem, M., Pauzner, R., Holtzman, E. J., Farfel, Z. <strong>Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation.</strong> J. Clin. Endocr. Metab. 89: 4025-4030, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15292344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15292344</a>] [<a href="https://doi.org/10.1210/jc.2004-0037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15292344">Mayan et al. (2004)</a> reported an extension of their previously described kindred (<a href="#8" class="mim-tip-reference" title="Mayan, H., Vered, M., Mouallem, M., Tzadok-Witkon, M., Pauzner, R., Farfel, Z. <strong>Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.</strong> J. Clin. Endocr. Metab. 87: 3248-3254, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12107233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12107233</a>] [<a href="https://doi.org/10.1210/jcem.87.7.8449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12107233">Mayan et al., 2002</a>) that contained 34 subjects, 18 of them affected by the Q565E mutation. Hypertension was diagnosed in 13 affected subjects at the age of 31 +/- 12 years. Five of the affected or obligatory affected subjects had stroke, in 4 between the ages of 50 and 62 years. Seven subjects with FHH were diagnosed 27 years previously. All 4 subjects who were normotensive at diagnosis had become hypertensive by follow-up. The mean time between detection of hyperkalemia and appearance of hypertension was 13 years. In the extended kindred, compared with the unaffected subjects, affected subjects had hyperkalemia, low transtubular potassium gradient, hyperchloremia, low bicarbonate, higher aldosterone, and marked suppression of renin. Urinary calcium levels in affected and unaffected subjects were 0.85 +/- 0.27 and 0.28 +/- 0.12 mmol/mmol creatinine, respectively. Hypercalciuria was accompanied by lower serum calcium levels, supporting a mechanism of renal calcium leak. The 6 affected, currently normotensive subjects had the same degree of hyperkalemia, hypercalciuria, and low renin as the affected hypertensive subjects. The authors concluded that in FHH with WNK4 mutations, with time all affected subjects will apparently develop hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12107233+15292344" 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">rs137853093 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853093;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=rs137853093" 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=rs137853093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with pseudohypoaldosteronism type IIB (PHA2B; <a href="/entry/614491">614491</a>), <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> identified a single basepair substitution in the WNK4 gene resulting in a glutamic acid-to-lysine substitution at codon 562 (E562K), within a highly conserved negatively charged 10-amino acid segment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family with pseudohypoaldosteronism type IIB (PHA2B; <a href="/entry/614491">614491</a>), <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> identified a single basepair substitution in the WNK4 gene resulting in an aspartic acid-to-alanine substitution at codon 564 (D564A), within a highly conserved negatively charged 10-amino acid segment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 PSEUDOHYPOALDOSTERONISM, TYPE IIB</strong>
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WNK4, ARG1185CYS
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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> rs137853095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853095;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/rs137853095?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=rs137853095" 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=rs137853095" 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=RCV000008102 OR RCV000731744" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008102, RCV000731744" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008102...</a>
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<p>In a family with pseudohypoaldosteronism type IIB (PHA2B; <a href="/entry/614491">614491</a>), <a href="#13" class="mim-tip-reference" title="Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. <strong>Human hypertension caused by mutations in WNK kinases.</strong> Science 293: 1107-1112, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>] [<a href="https://doi.org/10.1126/science.1062844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11498583">Wilson et al. (2001)</a> identified an arg-to-cys substitution at codon 1185 (R1185C) of the WNK4 gene, a codon just distal to the second putative coil domain. Arginine-1185 is conserved among WNK family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" 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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<br />
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<a id="references"class="mim-anchor"></a>
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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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<a id="Farfel1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Farfel, Z., Iaina, A., Rosenthal, T., Waks, U., Shibolet, S., Gafni, J.
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<strong>Familial hyperpotassemia and hypertension accompanied by normal plasma aldosterone levels: possible hereditary cell membrane defect.</strong>
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Arch. Intern. Med. 138: 1828-1832, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/718348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">718348</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=718348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="He2007" class="mim-anchor"></a>
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He, G., Wang, H.-R., Huang, S.-K., Huang, C.-L.
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<strong>Intersectin links WNK kinases to endocytosis of ROMK1.</strong>
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J. Clin. Invest. 117: 1078-1087, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17380208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17380208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17380208[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=17380208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI30087" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Kahle2004" class="mim-anchor"></a>
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<div class="">
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Kahle, K. T., MacGregor, G. G., Wilson, F. H., Van Hoek, A. N., Brown, D., Ardito, T., Kashgarian, M., Giebisch, G., Hebert, S. C., Boulpaep, E. L., Lifton, R. P.
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<strong>Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.</strong>
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Proc. Nat. Acad. Sci. 101: 14877-14882, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15465913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15465913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15465913[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=15465913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0406172101" target="_blank">Full Text</a>]
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<a id="Kahle2003" class="mim-anchor"></a>
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<div class="">
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Kahle, K. T., Wilson, F. H., Leng, Q., Lalioti, M. D., O'Connell, A. D., Dong, K., Rapson, A. K., MacGregor, G. G., Giebisch, G., Hebert, S. C., Lifton, R. P.
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<strong>WNK4 regulates the balance between renal NaCl reabsorption and K(+) secretion.</strong>
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Nature Genet. 35: 372-376, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14608358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14608358</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14608358" 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/ng1271" target="_blank">Full Text</a>]
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<a id="Lalioti2006" class="mim-anchor"></a>
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Lalioti, M. D., Zhang, J., Volkman, H. M., Kahle, K. T., Hoffmann, K. E., Toka, H. R., Nelson-Williams, C., Ellison, D. H., Flavell, R., Booth, C. J., Lu, Y., Geller, D. S., Lifton, R. P.
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<strong>Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.</strong>
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Nature Genet. 38: 1124-1132, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964266</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964266" 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/ng1877" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Mansfield1997" class="mim-anchor"></a>
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Mansfield, T. A., Simon, D. B., Farfel, Z., Bia, M., Tucci, J. R., Lebel, M., Gutkin, M., Vialettes, B., Christofilis, M. A., Kauppinen-Makelin, R., Mayan, H., Risch, N., Lifton, R. P.
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<strong>Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.</strong>
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Nature Genet. 16: 202-205, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171836" 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/ng0697-202" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Mayan2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mayan, H., Munter, G., Shaharabany, M., Mouallem, M., Pauzner, R., Holtzman, E. J., Farfel, Z.
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<strong>Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation.</strong>
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J. Clin. Endocr. Metab. 89: 4025-4030, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15292344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15292344</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15292344" 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/10.1210/jc.2004-0037" target="_blank">Full Text</a>]
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<a id="Mayan2002" class="mim-anchor"></a>
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Mayan, H., Vered, M., Mouallem, M., Tzadok-Witkon, M., Pauzner, R., Farfel, Z.
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<strong>Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.</strong>
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J. Clin. Endocr. Metab. 87: 3248-3254, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12107233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12107233</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12107233" 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/10.1210/jcem.87.7.8449" target="_blank">Full Text</a>]
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<a id="Mu2011" class="mim-anchor"></a>
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Mu, S. Y., Shimosawa, T., Ogura, S., Wang, H., Uetake, Y., Kawakami-Mori, F., Marumo, T., Yatomi, Y., Geller, D. S., Tanaka, H., Fujita, T.
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<strong>Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension.</strong>
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Nature Med. 17: 573-580, 2011. Note: Erratum: Nature Med. 17: 1020 only, 2011. Erratum: Nature Med. 18: 630 only, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21499270" 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/nm.2337" target="_blank">Full Text</a>]
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<a id="Ohta2009" class="mim-anchor"></a>
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Ohta, A., Rai, T., Yui, N., Chiga, M., Yang, S.-S., Lin, S.-H., Sohara, E., Sasaki, S., Uchida, S.
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<strong>Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.</strong>
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Hum. Molec. Genet. 18: 3978-3986, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633012</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19633012" 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/ddp344" target="_blank">Full Text</a>]
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<a id="Ring2007" class="mim-anchor"></a>
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Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., Volkman, H. M., Wilson, F. H., Hebert, S. C., Lifton, R. P.
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<strong>WNK4 regulates activity of the epithelial Na(+) channel in vitro and in vivo.</strong>
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Proc. Nat. Acad. Sci. 104: 4020-4024, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360470[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=17360470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0611727104" target="_blank">Full Text</a>]
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Ring, A. M., Leng, Q., Rinehart, J., Wilson, F. H., Kahle, K. T., Hebert, S. C., Lifton, R. P.
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<strong>An SGK1 site in WNK4 regulates Na(+) channel and K(+) channel activity and has implications for aldosterone signaling and K(+) homeostasis.</strong>
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Proc. Nat. Acad. Sci. 104: 4025-4029, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360471[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=17360471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0611728104" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Wilson2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P.
|
|
<strong>Human hypertension caused by mutations in WNK kinases.</strong>
|
|
Science 293: 1107-1112, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11498583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11498583</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1062844" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Wilson2003" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Wilson, F. H., Kahle, K. T., Sabath, E., Lalioti, M. D., Rapson, A. K., Hoover, R. S., Hebert, S. C., Gamba, G., Lifton, R. P.
|
|
<strong>Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 680-684, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12515852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12515852</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12515852[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=12515852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.242735399" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Wu2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<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: <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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|
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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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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Yang2003" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Yang, C.-L., Angell, J., Mitchell, R., Ellison, D. H.
|
|
<strong>WNK kinases regulate thiazide-sensitive Na-Cl cotransport.</strong>
|
|
J. Clin. Invest. 111: 1039-1045, 2003.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12671053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12671053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12671053[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=12671053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI17443" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
|
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<a id="Yang2007" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Yang, C.-L., Liu, X., Paliege, A., Zhu, X., Bachmann, S., Dawson, D. C., Ellison, D. H.
|
|
<strong>WNK1 and WNK4 modulate CFTR activity.</strong>
|
|
Biochem. Biophys. Res. Commun. 353: 535-540, 2007.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17194447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17194447</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17194447" 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.bbrc.2006.11.151" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Yang2007" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Yang, C.-L., Zhu, X., Ellison, D. H.
|
|
<strong>The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.</strong>
|
|
J. Clin. Invest. 117: 3403-3411, 2007.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17975670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17975670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17975670[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=17975670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI32033" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
|
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<a id="Yang2005" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Yang, C.-L., Zhu, X., Wang, Z., Subramanya, A. R., Ellison, D. H.
|
|
<strong>Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.</strong>
|
|
J. Clin. Invest. 115: 1379-1387, 2005.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15841204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15841204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15841204[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=15841204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI22452" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
|
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
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</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Patricia A. Hartz - updated : 11/3/2014
|
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</span>
|
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</div>
|
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</div>
|
|
<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">
|
|
Patricia A. Hartz - updated : 5/12/2011<br>George E. Tiller - updated : 8/6/2010<br>Patricia A. Hartz - updated : 1/17/2008<br>Patricia A. Hartz - updated : 10/18/2007<br>Patricia A. Hartz - updated : 4/24/2007<br>Patricia A. Hartz - updated : 4/11/2007<br>Victor A. McKusick - updated : 10/26/2006<br>John A. Phillips, III - updated : 7/21/2005<br>Marla J. F. O'Neill - updated : 5/20/2005<br>Patricia A. Hartz - updated : 11/22/2004<br>Victor A. McKusick - updated : 12/2/2003<br>Patricia A. Hartz - updated : 11/17/2003<br>Victor A. McKusick - updated : 2/21/2003<br>Ada Hamosh - updated : 8/28/2001<br>Ada Hamosh - updated : 8/14/2001
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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Victor A. McKusick : 6/2/1997
|
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
alopez : 05/17/2019
|
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</span>
|
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</div>
|
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</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
mgross : 11/07/2014<br>mcolton : 11/3/2014<br>alopez : 2/27/2012<br>alopez : 2/27/2012<br>carol : 12/16/2011<br>mgross : 5/13/2011<br>mgross : 5/13/2011<br>terry : 5/12/2011<br>wwang : 8/11/2010<br>terry : 8/6/2010<br>mgross : 2/5/2008<br>terry : 1/17/2008<br>terry : 1/17/2008<br>mgross : 10/18/2007<br>terry : 10/18/2007<br>wwang : 4/24/2007<br>wwang : 4/13/2007<br>terry : 4/11/2007<br>alopez : 10/30/2006<br>terry : 10/26/2006<br>alopez : 7/21/2005<br>wwang : 5/26/2005<br>carol : 5/26/2005<br>carol : 5/26/2005<br>carol : 5/26/2005<br>terry : 5/20/2005<br>mgross : 11/23/2004<br>mgross : 11/22/2004<br>alopez : 3/17/2004<br>alopez : 12/12/2003<br>terry : 12/2/2003<br>mgross : 11/17/2003<br>mgross : 2/21/2003<br>alopez : 8/31/2001<br>terry : 8/28/2001<br>alopez : 8/14/2001<br>terry : 8/14/2001<br>carol : 8/28/2000<br>carol : 9/16/1998<br>mark : 6/2/1997
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
|
<strong>*</strong> 601844
|
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</span>
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</h3>
|
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</div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
|
|
PROTEIN KINASE, LYSINE-DEFICIENT 4; WNK4
|
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|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
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</div>
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<div>
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<div >
|
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
PRKWNK4
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: WNK4</em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 17q21.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 17:42,780,610-42,797,066 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
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</p>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
17q21.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Pseudohypoaldosteronism, type IIB
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614491
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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|
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|
|
<span class="mim-text-font">
|
|
<p>WNK4 is an integrative regulator of renal electrolyte transport whose main target is the thiazide-sensitive Na-Cl cotransporter NCC (SLC12A3; 600968) (Wu and Peng, 2013). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</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>WNK4 is a serine-threonine protein kinase identified by Wilson et al. (2001) because of its homology to WNK1 (605232). Proteins encoded by WNK paralogs show high conservation in the kinase domain and have the distinctive substitution of cysteine for lysine in the active site. The encoded amino acid sequence of WNK4 showed 76% identity to WNK1 across a 370-amino acid segment spanning the kinase domain and the first putative coil domain, 51% identity across an 83-amino acid segment encompassing the C-terminal putative coil domain, and 52% identity across a 102-amino acid segment from residues 604 to 741 of WNK4. The intron-exon boundaries within these domains are conserved between the 2 genes. WNK4 is expressed virtually exclusively in the kidney, where it localizes to the distal convoluted tubule and the cortical collecting duct, adjacent segments of the distal nephron that play a key role in salt, water, potassium, and pH homeostasis. WNK4 is present exclusively in intracellular junctions in the distal convoluted tubule and in both the cytoplasm and intercellular junctions in the cortical collecting duct. WNK4 colocalizes with ZO1 (TJP1; 601009), a tight junction protein, but not with vinculin (193065), an adherens junction protein. Thus, Wilson et al. (2001) concluded that WNK4 is part of the tight junction complex. </p><p>By immunohistochemical analysis, Ring et al. (2007) showed Wnk4 expression in mouse distal colon and distal nephron. </p>
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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>The clinical features of type II pseudohypoaldosteronism (PHAII; see 145260), i.e., hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis, all depend on chloride anion. Furthermore, the observation that pseudohypoaldosteronism phenotypes resulting from WNK mutations constitute a 'mirror image' of the phenotypes resulting from loss-of-function mutations in NCC suggests that PHAII may result from increased SLC12A3 activity due to altered WNK signaling. By studies with heterologous expression of wildtype and mutant mouse Wnk4 in Xenopus oocytes, Wilson et al. (2003) demonstrated that Slc12a3 activity was inhibited by wildtype but not by mutant Wnk4. Wildtype Wnk4 inhibited Slc12a3 by reducing its expression on the membrane. Inhibition depended on Wnk4 kinase activity, because missense mutations that abrogated kinase function prevented the inhibition. PHAII-causing missense mutations further from the kinase domain also prevented the inhibition of Slc12a3 activity. Wilson et al. (2003) concluded that WNK4 negatively regulates the surface expression of SLC12A3, and the loss of this regulation may cause an inherited form of hypertension. </p><p>Independently, Yang et al. (2003) found that mouse Wnk4 reduced the plasma membrane association of Slc12a3 in injected Xenopus oocytes. However, they found that some Wnk4 mutations that cause PHAII retained the ability to inhibit Slc12a3. In addition, Yang et al. (2003) showed that Wnk1 (605232) did not affect Slc12a3-mediated sodium uptake in oocytes, but coexpression of Wnk1 with both Wnk4 and Slc12a3 restored sodium uptake to levels observed in oocytes expressing Slc12a3 alone. </p><p>To investigate the mechanisms by which WNK1 and WNK4 interact to regulate ion transport, Yang et al. (2005) performed experiments in HEK293 cells and Xenopus oocytes which showed that the WNK4 carboxyl terminus mediates SLC12A3 suppression, that the WNK1 kinase domain interacts with the WNK4 kinase domain, and that WNK1 inhibition of WNK4 is dependent on WNK1 catalytic activity and an intact WNK1 protein. </p><p>A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning as reported by Wilson et al. (2001) implicated the serine-threonine kinase WNK4 in this process. Wildtype WNK4 inhibits SLC12A3, the renal Na-Cl cotransporter (NCC); WNK4 mutations that cause type IIB pseudohypoaldosteronism relieve this inhibition. This explains the hypertension of that disorder but does not account for the hyperkalemia. By expression in Xenopus oocytes, Kahle et al. (2003) showed that WNK4 also inhibits the renal K+ channel ROMK (KCNJ1; 600359). This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of SLC12A3. Notably, the same mutations in WNK4 that relieve SLC12A3 inhibition markedly increase inhibition of ROMK. These findings established WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explained the pathophysiology of PHAII. The findings also identified WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis. </p><p>Kahle et al. (2004) determined that induction of wildtype mammalian Wnk4 reduced transepithelial resistance by increasing the absolute chloride permeability of preformed tight junctions. Wnk4 with a mutation in a residue critical for kinase activity had no effect. Wnk4 did not alter the flux of uncharged solutes, the expression or localization of tight junction proteins, or tight junction structure. Kahle et al. (2004) concluded that WNK4 coordinates tight junction permeability as well as transcellular ion flux to achieve NaCl and K+ homeostasis. </p><p>By coexpression in Xenopus oocytes, Ring et al. (2007) found that mouse Wnk4 inhibited the epithelial Na(+) channel (ENaC), the major mediator of aldosterone-sensitive Na(+) absorption, and that inhibition was independent of Wnk4 kinase activity. Inhibition required intact C termini in ENaC beta (SCNN1B; 600760)- and gamma (SCNN1G; 600761)-subunits, which contain PY motifs used to target ENaC for clearance from the plasma membrane. PHAII-causing mutations eliminated the ability of Wnk4 to inhibit ENaC. The colonic epithelium of mice harboring PHAII-mutant Wnk4 showed increased amiloride-sensitive Na(+) flux compared with wildtype littermates. Ring et al. (2007) concluded that ENaC is a downstream WNK4 target and that WNK4 regulates colonic Na(+) absorption. </p><p>Ring et al. (2007) showed that mouse Wnk4 is phosphorylated by Sgk1 (602958), a mediator of aldosterone signaling, at a site C-terminal to the second coiled-coil domain. A Wnk4 mutant that mimics phosphorylation at the Sgk1 site alleviated inhibition of both ENaC and ROMK channels, resulting in increased K(+) secretion. Ring et al. (2007) concluded that WNK4 has a role in mediating the aldosterone response to hyperkalemia. </p><p>Yang et al. (2007) noted that WNK1, WNK4, and the kidney-specific WNK1 isoform interact to regulate SLC12A3 activity, suggesting that WNKs form a signaling complex. They found that human WNK3 (300358), which is expressed by distal tubule cells, interacted with rodent Wnk1 and Wnk4 to regulate SLC12A3 in cultured kidney cells and Xenopus oocytes. Regulation of SLC12A3 in oocytes resulted from antagonism between WNK3 and Wnk4. A PHAII-associated mutation in Wnk4 exerted a dominant-negative effect on wildtype Wnk4 that mimicked WNK3 excess. </p><p>He et al. (2007) showed that mammalian Wnk1 and Wnk4 interacted with the endocytic scaffold protein intersectin-1 (ITSN1; 602442) and that these interactions were crucial for stimulation of Romk1 endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4 required their proline-rich motifs, but it did not require their kinase activities. PHAII-causing mutations in Wnk4 enhanced the interactions of Wnk4 with Itsn1 and Romk1, leading to increased endocytosis of Romk1. </p><p>Yang et al. (2007) showed that coexpression of rodent Wnk1 and Wnk4 with human CFTR (602421) suppressed CFTR-dependent chloride channel activity in Xenopus oocytes. The effect of Wnk4 was dose dependent, independent of Wnk4 kinase activity, and occurred, at least in part, by reducing CFTR protein abundance at the plasma membrane. In contrast, the effect of Wnk1 on CFTR activity required Wnk1 kinase activity. Moreover, Wnk1 and Wnk4 exhibited additive CFTR inhibition. Mouse Wnk4 with a PHAII-associated mutation was a more potent inhibitor of CFTR activity than wildtype Wnk4. </p><p>Using rodent models of salt-induced hypertension and cultured mouse distal collecting tubule cells, Mu et al. (2011) found that beta-2 adrenergic receptor (ADRB2; 109690) stimulation led to decreased transcription of Wnk4. Adrb2 stimulation resulted in cyclic AMP-dependent inhibition of histone deacetylase-8 (HDAC8; 300269), which permitted increased occupancy of the Wnk4 promoter region by acetylated histones H3 and H4 and the binding of glucocorticoid receptor (GCCR; 138040) to negative glucocorticoid-responsive elements in the Wnk4 promoter. Downregulation of Wnk4 caused Ncc and ENaC activation, sodium retention, and salt-induced hypertension. </p><p>KLHL3 (605775) and CUL3 (603136) are part of a cullin-RING ubiquitin E3 ligase complex that targets renal electrolyte transporters or their regulators. 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. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Wilson et al. (2001) determined that the WNK4 gene comprises 19 exons contained within 16 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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<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>Wilson et al. (2001) localized the WNK4 gene to the interval on chromosome 17 between loci D17S250 and D17S579, both of which lie within the minimum genetic interval containing the PHA2B (614491) locus on chromosome 17. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wilson et al. (2001) identified 4 missense mutations in the WNK4 gene (601844.0001-601844.0004) in patients with pseudohypoaldosteronism type IIB (PHA2B). Three of these are charge-changing substitutions that cluster in a span of 4 amino acids just distal to the first putative coil domain, within a negatively charged 10-amino acid segment that is highly conserved among all members of the WNK family in human as well as orthologs in mouse and rat. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The causes of hypertension have been obscure owing to the physiologic complexity of the trait. Investigation of mendelian forms of high and low blood pressure has implicated variation in renal salt handling in the pathogenesis of hypertension in humans. Pseudohypoaldosteronism type II (see 145260) can be caused by mutations in WNK1 or WNK4. Renal expression of both genes is confined to epithelia of the distal nephron--the distal convoluted tubule (DCT), the connecting tubule (CNT), and collecting duct. These observations suggested and in vitro studies supported the idea that the Wnks might regulate Na+, Cl-, and K+ flux pathways in these nephron segments. Lalioti et al. (2006) showed that renal physiology in mice transgenic for genomic segments harboring wildtype or PHAII mutant Wnk4 is changed in opposite directions: the mice with the PHAII genomic segment had higher blood pressure, hyperkalemia, hypercalciuria, and marked hyperplasia of the DCT, whereas the opposite was true in transgenic mice with the wildtype genomic segment. Genetic deficiency of the Na-Cl cotransporter (NCC) of the DCT reversed phenotypes seen in the mice carrying the PHAII genomic segment, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings established that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC. </p><p>Ohta et al. (2009) generated Wnk4-hypomorphic mice by deleting exon 7 of the Wnk4 gene. These mice did not show hypokalemia and metabolic alkalosis but did exhibit low blood pressure and increased sodium and potassium excretion under low-salt diet. Phosphorylation of Osr1 (OXSR1; 604046)/Spak (STK39; 607648) and Ncc was significantly reduced in the mutant mice as compared with their wildtype littermates. Protein levels of Romk and maxi-K (KCNMA1; 600150) were not changed, but the epithelial sodium channel (ENaC) appeared to be activated as a compensatory mechanism for the reduced Ncc function. Ohta et al. (2009) concluded that wildtype WNK4 is a positive regulator for the WNK-OSR1/SPAK-NCC cascade and is a potential target of antihypertensive drugs. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>4 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PSEUDOHYPOALDOSTERONISM, TYPE IIB</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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WNK4, GLN565GLU
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<br />
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SNP: rs137853092,
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ClinVar: RCV000008099
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with autosomal dominant pseudohypoaldosteronism type IIB (PHA2B; 614491) previously described by Farfel et al. (1978) and further characterized by Mansfield et al. (1997), Wilson et al. (2001) identified a C-to-G substitution in the WNK4 gene resulting in a glutamine-to-glutamic acid substitution at codon 565 (Q565E), within a highly conserved negatively charged 10-amino acid segment. </p><p>Mayan et al. (2004) reported an extension of their previously described kindred (Mayan et al., 2002) that contained 34 subjects, 18 of them affected by the Q565E mutation. Hypertension was diagnosed in 13 affected subjects at the age of 31 +/- 12 years. Five of the affected or obligatory affected subjects had stroke, in 4 between the ages of 50 and 62 years. Seven subjects with FHH were diagnosed 27 years previously. All 4 subjects who were normotensive at diagnosis had become hypertensive by follow-up. The mean time between detection of hyperkalemia and appearance of hypertension was 13 years. In the extended kindred, compared with the unaffected subjects, affected subjects had hyperkalemia, low transtubular potassium gradient, hyperchloremia, low bicarbonate, higher aldosterone, and marked suppression of renin. Urinary calcium levels in affected and unaffected subjects were 0.85 +/- 0.27 and 0.28 +/- 0.12 mmol/mmol creatinine, respectively. Hypercalciuria was accompanied by lower serum calcium levels, supporting a mechanism of renal calcium leak. The 6 affected, currently normotensive subjects had the same degree of hyperkalemia, hypercalciuria, and low renin as the affected hypertensive subjects. The authors concluded that in FHH with WNK4 mutations, with time all affected subjects will apparently develop hypertension. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PSEUDOHYPOALDOSTERONISM, TYPE IIB</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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WNK4, GLU562LYS
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<br />
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SNP: rs137853093,
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ClinVar: RCV000008100
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with pseudohypoaldosteronism type IIB (PHA2B; 614491), Wilson et al. (2001) identified a single basepair substitution in the WNK4 gene resulting in a glutamic acid-to-lysine substitution at codon 562 (E562K), within a highly conserved negatively charged 10-amino acid segment. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PSEUDOHYPOALDOSTERONISM, TYPE IIB</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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WNK4, ASP564ALA
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<br />
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SNP: rs137853094,
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ClinVar: RCV000008101
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with pseudohypoaldosteronism type IIB (PHA2B; 614491), Wilson et al. (2001) identified a single basepair substitution in the WNK4 gene resulting in an aspartic acid-to-alanine substitution at codon 564 (D564A), within a highly conserved negatively charged 10-amino acid segment. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 PSEUDOHYPOALDOSTERONISM, TYPE IIB</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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WNK4, ARG1185CYS
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<br />
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SNP: rs137853095,
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gnomAD: rs137853095,
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ClinVar: RCV000008102, RCV000731744
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with pseudohypoaldosteronism type IIB (PHA2B; 614491), Wilson et al. (2001) identified an arg-to-cys substitution at codon 1185 (R1185C) of the WNK4 gene, a codon just distal to the second putative coil domain. Arginine-1185 is conserved among WNK 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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Farfel, Z., Iaina, A., Rosenthal, T., Waks, U., Shibolet, S., Gafni, J.
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<strong>Familial hyperpotassemia and hypertension accompanied by normal plasma aldosterone levels: possible hereditary cell membrane defect.</strong>
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Arch. Intern. Med. 138: 1828-1832, 1978.
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[PubMed: 718348]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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He, G., Wang, H.-R., Huang, S.-K., Huang, C.-L.
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<strong>Intersectin links WNK kinases to endocytosis of ROMK1.</strong>
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J. Clin. Invest. 117: 1078-1087, 2007.
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[PubMed: 17380208]
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[Full Text: https://doi.org/10.1172/JCI30087]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kahle, K. T., MacGregor, G. G., Wilson, F. H., Van Hoek, A. N., Brown, D., Ardito, T., Kashgarian, M., Giebisch, G., Hebert, S. C., Boulpaep, E. L., Lifton, R. P.
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<strong>Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.</strong>
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Proc. Nat. Acad. Sci. 101: 14877-14882, 2004.
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[PubMed: 15465913]
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[Full Text: https://doi.org/10.1073/pnas.0406172101]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kahle, K. T., Wilson, F. H., Leng, Q., Lalioti, M. D., O'Connell, A. D., Dong, K., Rapson, A. K., MacGregor, G. G., Giebisch, G., Hebert, S. C., Lifton, R. P.
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<strong>WNK4 regulates the balance between renal NaCl reabsorption and K(+) secretion.</strong>
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|
Nature Genet. 35: 372-376, 2003.
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[PubMed: 14608358]
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[Full Text: https://doi.org/10.1038/ng1271]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lalioti, M. D., Zhang, J., Volkman, H. M., Kahle, K. T., Hoffmann, K. E., Toka, H. R., Nelson-Williams, C., Ellison, D. H., Flavell, R., Booth, C. J., Lu, Y., Geller, D. S., Lifton, R. P.
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Mayan, H., Vered, M., Mouallem, M., Tzadok-Witkon, M., Pauzner, R., Farfel, Z.
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<strong>Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.</strong>
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Mu, S. Y., Shimosawa, T., Ogura, S., Wang, H., Uetake, Y., Kawakami-Mori, F., Marumo, T., Yatomi, Y., Geller, D. S., Tanaka, H., Fujita, T.
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<strong>Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension.</strong>
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Ohta, A., Rai, T., Yui, N., Chiga, M., Yang, S.-S., Lin, S.-H., Sohara, E., Sasaki, S., Uchida, S.
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<strong>Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.</strong>
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Hum. Molec. Genet. 18: 3978-3986, 2009.
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Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., Volkman, H. M., Wilson, F. H., Hebert, S. C., Lifton, R. P.
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<strong>WNK4 regulates activity of the epithelial Na(+) channel in vitro and in vivo.</strong>
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Proc. Nat. Acad. Sci. 104: 4020-4024, 2007.
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Ring, A. M., Leng, Q., Rinehart, J., Wilson, F. H., Kahle, K. T., Hebert, S. C., Lifton, R. P.
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<strong>An SGK1 site in WNK4 regulates Na(+) channel and K(+) channel activity and has implications for aldosterone signaling and K(+) homeostasis.</strong>
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Proc. Nat. Acad. Sci. 104: 4025-4029, 2007.
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Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P.
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<strong>Human hypertension caused by mutations in WNK kinases.</strong>
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Science 293: 1107-1112, 2001.
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Wilson, F. H., Kahle, K. T., Sabath, E., Lalioti, M. D., Rapson, A. K., Hoover, R. S., Hebert, S. C., Gamba, G., Lifton, R. P.
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<strong>Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.</strong>
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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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Yang, C.-L., Angell, J., Mitchell, R., Ellison, D. H.
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Yang, C.-L., Liu, X., Paliege, A., Zhu, X., Bachmann, S., Dawson, D. C., Ellison, D. H.
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<strong>WNK1 and WNK4 modulate CFTR activity.</strong>
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[PubMed: 17194447]
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Yang, C.-L., Zhu, X., Ellison, D. H.
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<strong>The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.</strong>
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Yang, C.-L., Zhu, X., Wang, Z., Subramanya, A. R., Ellison, D. H.
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<strong>Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.</strong>
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