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Entry
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- *605232 - PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
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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">*605232</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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<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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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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/605232">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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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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<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=ENSG00000060237;t=ENST00000315939" 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=65125" 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=605232" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000060237;t=ENST00000315939" 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_001184985,NM_014823,NM_018979,NM_213655,XM_006719003,XM_011520997,XM_011520998,XM_011520999,XM_011521000,XM_011521001,XM_011521002,XM_011521003,XM_011521006,XM_011521007,XM_011521008,XM_011521009,XM_017019834,XM_017019835,XM_017019836,XM_017019837,XM_017019838,XM_047429374,XM_047429375,XM_047429376,XM_047429377,XM_047429378,XM_047429379,XM_047429380,XM_047429381,XM_047429382,XM_047429383,XM_047429384,XM_047429385,XM_047429386,XM_047429387,XM_047429388,XM_047429389,XM_047429390,XM_047429391,XM_047429392,XM_047429393,XM_047429394,XM_047429395,XM_047429396,XM_047429397,XM_047429398,XM_047429399,XM_047429400,XM_047429401,XM_047429402,XM_047429403" 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_018979" 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=605232" 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=05570&isoform_id=05570_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/WNK1" 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/6933864,11125348,20521007,29134528,34783914,46102592,119024965,119024967,119024969,119024971,119609357,119609358,119609359,119609360,119609361,119609362,119609363,119609364,120659888,120660386,146424354,239740381,239740382,239740383,296453029,296939600,296939602,296939604,300797780,374111529,578822662,767971427,767971429,767971431,767971433,767971435,767971437,767971439,767971445,767971447,767971449,767971451,1034581204,1034581206,1034581208,1034581210,1034581212,2217290573,2217290576,2217290579,2217290583,2217290585,2217290589,2217290591,2217290593,2217290595,2217290597,2217290599,2217290601,2217290603,2217290605,2217290607,2217290610,2217290612,2217290616,2217290618,2217290620,2217290623,2217290626,2217290628,2217290630,2217290634,2217290636,2217290638,2217290640,2217290642,2217290644,2462533791,2462533793,2462533795,2462533797,2462533799,2462533801,2462533803,2462533805,2462533807,2462533809,2462533811,2462533813,2462533815,2462533817,2462533819,2462533821,2462533823,2462533825,2462533827,2462533829,2462533831,2462533833,2462533835,2462533837,2462533839,2462533841,2462533843,2462533845,2462533847,2462533849,2462533851,2462533853,2462533855,2462533857,2462533859,2462533861,2462533863,2462533865,2462533867,2462533869,2462533871,2462533873,2462533875,2462533877,2462533879,2462533881,2462533883" 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/Q9H4A3" 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=65125" 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=ENSG00000060237;t=ENST00000315939" 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=WNK1" 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=WNK1" 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+65125" 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/WNK1" 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:65125" 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/65125" 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=chr12&hgg_gene=ENST00000340908.9&hgg_start=752579&hgg_end=911452&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:14540" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/wnk1" 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=605232[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=605232[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/WNK1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000060237" 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=WNK1" 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=WNK1" 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=WNK1" 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=WNK1&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/PA33782" 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:14540" 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:2442092" 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/WNK1#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:2442092" 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/65125/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=65125" 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-030131-2656" 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:65125" 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=WNK1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 860809000<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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605232
|
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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 1; WNK1
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
PROSTATE-DERIVED STERILE 20-LIKE KINASE; PSK<br />
|
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PRKWNK1<br />
|
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KDP<br />
|
|
KIAA0344
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
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WNK1/HSN2 ISOFORM, INCLUDED
|
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</span>
|
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</div>
|
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=WNK1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">WNK1</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">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/10?start=-3&limit=10&highlight=10">12p13.33</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:752579-911452&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'})">12:752,579-911,452</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
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Neuropathy, hereditary sensory and autonomic, type II
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p><a href="#13" class="mim-tip-reference" title="Nagase, T., Ishikawa, I., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., O'Hara, O. <strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 4: 141-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>] [<a href="https://doi.org/10.1093/dnares/4.2.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205841">Nagase et al. (1997)</a> cloned a WNK1 cDNA, which they called KIAA0344. The deduced protein contains 1,246 amino acids. RT-PCR detected highest expression in kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9205841" 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 degenerate PCR against conserved kinase catalytic subdomains, <a href="#12" class="mim-tip-reference" title="Moore, T. M., Garg, R., Johnson, C., Coptcoat, M. J., Ridley, A. J., Morris, J. D. H. <strong>PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization.</strong> J. Biol. Chem. 275: 4311-4322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10660600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10660600</a>] [<a href="https://doi.org/10.1074/jbc.275.6.4311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10660600">Moore et al. (2000)</a> cloned human WNK1, which they called PSK. PSK belongs to the STE20 family of serine-threonine kinases. The PSK protein contains 1,235 amino acids and has an N-terminal kinase domain. PSK was ubiquitously expressed in all tissues examined by Northern blot analysis, with strongest expression in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10660600" 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="#23" class="mim-tip-reference" title="Xu, B., English, J. M., Wilsbacher, J. L., Stippec, S., Goldsmith, E. J., Cobb, M. H. <strong>WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.</strong> J. Biol. Chem. 275: 16795-16801, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10828064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10828064</a>] [<a href="https://doi.org/10.1074/jbc.275.22.16795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10828064">Xu et al. (2000)</a> isolated a full-length rat cDNA encoding Wnk1 and identified homologs in various species, including partial human sequences. The N-terminal half of the deduced 2,126-amino acid rat protein has a proline-rich region, followed by a serine/threonine kinase domain and coiled-coil region, and the C-terminal half has a proline-rich region and coiled-coil region. Wnk1 contains a cysteine instead of the usual lysine at a key position in its active site. Immunoblot analysis detected an endogenous 230-kD protein in rat brain and several mammalian cell lines, including human embryonic kidney (HEK293) cells. Most endogenous WNK1 protein was found in the particulate fraction of HEK293 cells, suggesting that WNK1 is associated with membranes or the cytoskeleton. Immunofluorescence analysis of HEK293 cells transfected with rat Wnk1 revealed cytoplasmic staining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10828064" 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="#21" 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> noted that the deduced human and rat WNK1 proteins share 86% identity. By Northern blot analysis, they observed expression of human WNK1 in most tissues, with 2 predominant isoforms: a 10-kb transcript expressed at high levels in the kidney, and a 12-kb transcript predominant in heart and skeletal muscle. By immunofluorescence microscopy, <a href="#21" 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> demonstrated that WNK1 localizes to the distal convoluted tubule and the cortical collecting duct, and is also abundant in the medullary collecting duct. <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><a href="#3" class="mim-tip-reference" title="Choate, K. A., Kahle, K. T., Wilson, F. H., Nelson-Williams, C., Lifton, R. P. <strong>WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl(-)-transporting epithelia.</strong> Proc. Nat. Acad. Sci. 100: 663-668, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12522152[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.242728499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522152">Choate et al. (2003)</a> examined the distribution of WNK1 in extrarenal tissues. Immunostaining using WNK1-specific antibodies demonstrated that WNK1 was not present in all cell types; rather, it was predominantly localized in polarized epithelia, including those lining the lumen of the hepatic biliary ducts, pancreatic ducts, epididymis, sweat ducts, colonic crypts, and gallbladder. WNK1 was also found in the basal layers of epidermis and throughout the esophageal epithelium. Subcellular localization of WNK1 varied among these epithelia. WNK1 was cytoplasmic in kidney, colon, gallbladder, sweat duct, skin, and esophagus. In contrast, it localized to the lateral membrane in bile ducts, pancreatic ducts, and epididymis. These epithelia are all notable for their prominent role in chloride-iron flux. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522152" 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 primer extension with human leukocyte and kidney RNA, 5-prime RACE of human heart and kidney cDNA libraries, and RT-PCR of human heart, skeletal muscle, and kidney RNA, <a href="#5" class="mim-tip-reference" title="Delaloy, C., Lu, J., Houot, A.-M., Disse-Nicodeme, S., Gasc, J.-M., Corvol, P., Jeunemaitre, X. <strong>Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.</strong> Molec. Cell. Biol. 23: 9208-9221, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645531</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14645531[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/10.1128/MCB.23.24.9208-9221.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14645531">Delaloy et al. (2003)</a> characterized several WNK1 variants resulting from tissue-specific splicing and the use of multiple transcriptional start sites and polyadenylation sites. Two promoters in exon 1 generate 2 ubiquitously expressed WNK1 isoforms with complete kinase domains. A third promoter in exon 4A generates a kidney-specific transcript that encodes an N-terminally truncated protein that is kinase defective. Exon 4A is highly conserved between human and rodents and encodes a cysteine-rich region. Northern blot analysis detected a 9-kb transcript expressed predominantly in human kidney and a 10.5-kb transcript expressed predominantly in skeletal muscle, heart, and brain. Qualitative RT-PCR detected 10 times more kinase-defective transcript than kinase domain-containing transcript in human kidney mRNA. In situ hybridization of adult mouse kidney using an exon 4A-specific probe revealed expression in kidney cortex, predominantly in distal convoluted tubules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>WNK1/HSN2 Isoform</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> identified a novel gene, which they designated HSN2, within the hereditary sensory neuropathy type II (HSAN2; <a href="/entry/201300">201300</a>) critical region on 12p13.33. The HSN2 gene encodes a deduced 434-amino acid protein. Northern blot analysis of adult human tissues failed to detect HSN2 transcripts, suggesting that the gene might be expressed at very low levels. <a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> suggested that the HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060842" 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 Northern blot and RT-PCR analysis using mouse Wnk1, <a href="#17" class="mim-tip-reference" title="Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A. <strong>Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.</strong> J. Clin. Invest. 118: 2496-2505, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18521183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18521183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18521183[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/JCI34088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18521183">Shekarabi et al. (2008)</a> concluded that HSN2 is an alternatively spliced exon of WNK1 and is part of a nervous system-specific isoform of WNK1, which they called WNK1/HSN2. Northern blot analysis of mouse tissues showed a 10-kb transcript exclusively expressed in nervous system tissues, including the spinal cord, brain, and dorsal root ganglia. RT-PCR analysis demonstrated that the Wnk1/Hsn2 isoform includes either the Hsn2 exon alone or Hsn2 along with a novel exon 8B and lacks exons 11 and 12. Immunohistochemical studies confirmed localization of the Wnk1/Hsn2 isoform to mouse nervous system tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18521183" 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="#21" 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 WNK1 gene contains 28 exons that span 156 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><p><a href="#5" class="mim-tip-reference" title="Delaloy, C., Lu, J., Houot, A.-M., Disse-Nicodeme, S., Gasc, J.-M., Corvol, P., Jeunemaitre, X. <strong>Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.</strong> Molec. Cell. Biol. 23: 9208-9221, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645531</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14645531[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/10.1128/MCB.23.24.9208-9221.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14645531">Delaloy et al. (2003)</a> identified 2 promoters in exon 1 of the WNK1 gene, including 1 within the coding region, that generate ubiquitously expressed WNK1 transcripts. A third promoter, located in the alternative exon 4A within intron 4, generates a kidney-specific transcript. The promoters lack TATA boxes, are GC-rich, and contain several transcription factor-binding sites. A repressor element is present in the most 5-prime promoter in exon 1. In addition, WNK1 has multiple transcription start sites in exon 1 and 2 polyadenylation sites at its 3-prime end. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>WNK1/HSN2 Isoform</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> determined that the HSN2 gene consists of a single exon that is located within intron 8 of the WNK1 gene and transcribed from the same strand. The authors initially concluded that the WNK1 and HSN2 genes were differentially regulated. Subsequently, <a href="#17" class="mim-tip-reference" title="Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A. <strong>Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.</strong> J. Clin. Invest. 118: 2496-2505, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18521183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18521183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18521183[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/JCI34088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18521183">Shekarabi et al. (2008)</a> determined that HSN2 is a nervous-system specific exon of the WNK1 gene, and they identified a novel exon 8B. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15060842+18521183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By analysis of a radiation hybrid panel, <a href="#13" class="mim-tip-reference" title="Nagase, T., Ishikawa, I., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., O'Hara, O. <strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 4: 141-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>] [<a href="https://doi.org/10.1093/dnares/4.2.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205841">Nagase et al. (1997)</a> mapped the WNK1 gene to chromosome 12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9205841" 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="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 10/19/2016."None>Gross (2016)</a> mapped the WNK1 gene to chromosome 12p13.33 based on an alignment of the WNK1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AJ296290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AJ296290</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#12" class="mim-tip-reference" title="Moore, T. M., Garg, R., Johnson, C., Coptcoat, M. J., Ridley, A. J., Morris, J. D. H. <strong>PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization.</strong> J. Biol. Chem. 275: 4311-4322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10660600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10660600</a>] [<a href="https://doi.org/10.1074/jbc.275.6.4311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10660600">Moore et al. (2000)</a> found that immunoprecipitated PSK phosphorylated myelin basic protein (<a href="/entry/159430">159430</a>) and transfected PSK-stimulated MKK4 (<a href="/entry/601335">601335</a>) and MKK7 (<a href="/entry/603014">603014</a>), and activated the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway (see <a href="/entry/603014">603014</a>). Microinjection of PSK into cells resulted in localization of PSK to a vesicular compartment and caused a marked reduction in actin stress fibers. In contrast, C-terminally truncated PSK did not localize to this compartment or induce a decrease in stress fibers, demonstrating a requirement for the C terminus. Kinase-defective PSK, carrying a lys57-to-ala (K57A) mutation, was unable to reduce stress fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10660600" 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="#22" class="mim-tip-reference" title="Xu, B. E., Min, X., Stippec, S., Lee, B. H., Goldsmith, E. J., Cobb, M. H. <strong>Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.</strong> J. Biol. Chem. 277: 48456-48462, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12374799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12374799</a>] [<a href="https://doi.org/10.1074/jbc.M207917200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12374799">Xu et al. (2002)</a> expressed fragments of rat Wnk1 in bacteria and identified an autoinhibitory region just C-terminal to the kinase domain. The isolated autoinhibitory domain, which is conserved in all 4 human WNKs, suppressed the activity of the Wnk1 kinase domain. Mutation of 2 conserved phenylalanines in the autoinhibitory domain (phe524 and phe526 in rat Wnk1) attenuated its ability to inhibit Wnk1 kinase activity, and the same mutations in a Wnk1 fragment containing the autoinhibitory domain increased its kinase activity. Wnk1 expressed in bacteria was autophosphorylated, and autophosphorylation of ser382 in the activation loop was required for its activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12374799" 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="#25" 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 (<a href="/entry/601844">601844</a>) reduced the plasma membrane association of the thiazide-sensitive sodium-chloride cotransporter (NCC, or SLC12A3; <a href="/entry/600968">600968</a>) in injected Xenopus oocytes. They further demonstrated that Wnk1 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="#28" 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 C 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 href="#27" 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 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="#10" class="mim-tip-reference" title="Lee, B.-H., Min, X., Heise, C. J., Xu, B., Chen, S., Shu, H., Luby-Phelps, K., Goldsmith, E. J., Cobb, M. H. <strong>WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding.</strong> Molec. Cell 15: 741-751, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15350218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15350218</a>] [<a href="https://doi.org/10.1016/j.molcel.2004.07.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15350218">Lee et al. (2004)</a> found that rat Wnk1 selectively bound to and phosphorylated synaptotagmin-2 (SYT2; <a href="/entry/600104">600104</a>) calcium-binding C2 domains. Endogenous Wnk1 and Syt2 coimmunoprecipitated and colocalized on a subset of secretory granules in a rat insulinoma cell line. Phosphorylation by Wnk1 increased the amount of Ca(2+) required for Syt2 binding to phospholipid vesicles. <a href="#10" class="mim-tip-reference" title="Lee, B.-H., Min, X., Heise, C. J., Xu, B., Chen, S., Shu, H., Luby-Phelps, K., Goldsmith, E. J., Cobb, M. H. <strong>WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding.</strong> Molec. Cell 15: 741-751, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15350218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15350218</a>] [<a href="https://doi.org/10.1016/j.molcel.2004.07.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15350218">Lee et al. (2004)</a> concluded that phosphorylation of SYT2 by WNK1 can regulate Ca(2+) sensing and the subsequent Ca(2+)-dependent interactions mediated by synaptotagmin C2 domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15350218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Lenertz, L. Y., Lee, B.-H., Min, X., Xu, B., Wedin, K., Earnest, S., Goldsmith, E. J., Cobb, M. H. <strong>Properties of WNK1 and implications for other family members.</strong> J. Biol. Chem. 280: 26653-26658, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15883153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15883153</a>] [<a href="https://doi.org/10.1074/jbc.M502598200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15883153">Lenertz et al. (2005)</a> found that hypertonic stress activated rat Wnk1 when it was expressed in kidney epithelial cells and breast and colon cancer cell lines. Hypotonic stress led to a modest increase in Wnk1 activity. Gel filtration suggested that Wnk1 exists as a tetramer, and yeast 2-hybrid analysis revealed interaction between residues 1 to 222 of the Wnk1 N terminus and Wnk1 residues 481 to 660, which contain the autoinhibitory domain and a coiled-coil region. <a href="#11" class="mim-tip-reference" title="Lenertz, L. Y., Lee, B.-H., Min, X., Xu, B., Wedin, K., Earnest, S., Goldsmith, E. J., Cobb, M. H. <strong>Properties of WNK1 and implications for other family members.</strong> J. Biol. Chem. 280: 26653-26658, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15883153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15883153</a>] [<a href="https://doi.org/10.1074/jbc.M502598200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15883153">Lenertz et al. (2005)</a> found no direct interaction between Wnk1 and Wnk4, but Wnk1 phosphorylated both Wnk2 (<a href="/entry/606249">606249</a>) and Wnk4, and the Wnk1 autoinhibitory domain inhibited the catalytic activities of Wnk2 and Wnk4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15883153" 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 Xenopus oocytes and Chinese hamster ovary cells, <a href="#24" class="mim-tip-reference" title="Xu, B., Stippec, S., Chu, P.-Y., Lazrak, A., Li, X.-J., Lee, B.-H., English, J. M., Ortega, B., Huang, C.-L., Cobb, M. H. <strong>WNK1 activates SGK1 to regulate the epithelial sodium channel.</strong> Proc. Nat. Acad. Sci. 102: 10315-10320, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16006511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16006511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16006511[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.0504422102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16006511">Xu et al. (2005)</a> showed that WNK1 controls ion permeability by activating SGK1 (<a href="/entry/602958">602958</a>), leading to activation of the epithelial sodium channel (see SCNN1A; <a href="/entry/600228">600228</a>). Increased WNK1-induced channel activity depended on SGK1 and the E3 ubiquitin ligase, NEDD4-2 (NEDD4L; <a href="/entry/606384">606384</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16006511" 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>Alternative splicing of WNK1 produces a kidney-specific short form that lacks a kinase domain, KS-WNK1, and a more ubiquitous long form, L-WNK1. Using reconstitution studies in Xenopus oocytes, <a href="#20" class="mim-tip-reference" title="Wade, J. B., Fang, L., Liu, J., Li, D., Yang, C.-L., Subramanya, A. R., Maouyo, D., Mason, A., Ellison, D. H., Welling, P. A. <strong>WNK1 kinase isoform switch regulates renal potassium excretion.</strong> Proc. Nat. Acad. Sci. 103: 8558-8563, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16709664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16709664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16709664[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.0603109103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16709664">Wade et al. (2006)</a> found that rat L-Wnk1 inhibited the K+ channel Kir1.1 (KCNJ1; <a href="/entry/600359">600359</a>) by reducing its cell surface localization, and this inhibition required an intact kinase domain. Ks-Wnk1 did not directly alter Kir1.1 channel activity, but it acted as a dominant-negative inhibitor of L-Wnk1 and released Kir1.1 from inhibition. Acute dietary potassium loading in rats increased the relative abundance of Ks-Wnk1 to L-Wnk1 transcript and protein in kidney, indicating that physiologic upregulation of Kir1.1 activity involves a WNK1 isoform switch. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16709664" 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 yeast 2-hybrid analysis of Jurkat human T cells and immunoprecipitation analysis of human embryonic kidney cells and HeLa cells, <a href="#1" class="mim-tip-reference" title="Anselmo, A. N., Earnest, S., Chen, W., Juang, Y.-C., Kim, S. C., Zhao, Y., Cobb, M. H. <strong>WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.</strong> Proc. Nat. Acad. Sci. 103: 10883-10888, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16832045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16832045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16832045[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.0604607103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16832045">Anselmo et al. (2006)</a> showed that OSR1 (OXSR1; <a href="/entry/604046">604046</a>) and WNK1 interacted through conserved C-terminal motifs. OSR1 was phosphorylated in a WNK1-dependent manner, and depletion of WNK1 from HeLa cells with small interfering RNA reduced OSR1 kinase activity. Depletion of either WNK1 or OSR1 reduced Na-K-Cl cotransporter (NKCC; see <a href="/entry/600839">600839</a>) activity, suggesting that WNK1 and OSR1 are required for NKCC function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16832045" 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="#8" 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 (KCNJ1) endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4 required their proline-rich motifs, but it did not require their kinase activities. Pseudohypoaldosteronism II (<a href="/entry/145260">145260</a>)-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="#26" 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. <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>
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<p><strong><em>Pseudohypoaldosteronism Type IIC</em></strong></p><p>
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<a href="#21" 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 WNK1 as the gene mutant in one form of pseudohypoaldosteronism type II (PHA2C; <a href="/entry/614492">614492</a>), an autosomal dominant disorder characterized by hypertension, hyperkalemia, and renal tubular acidosis. In a 10-member kindred segregating PHAII, they identified a 41-kb deletion in intron 1 of WNK1 (<a href="#0001">605232.0001</a>). In the family previously described by <a href="#6" class="mim-tip-reference" title="Disse-Nicodeme, S., Achard, J.-M., Desitter, I., Houot, A.-M., Fournier, A., Corvol, P., Jeunemaitre, X. <strong>A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension.</strong> Am. J. Hum. Genet. 67: 302-310, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10869238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10869238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10869238[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/10.1086/303020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10869238">Disse-Nicodeme et al. (2000)</a>, they identified a 22-kb deletion within intron 1 of WNK1 (<a href="#0002">605232.0002</a>). <a href="#21" 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> found that affected individuals carrying the 22-kb deletion had a 5-fold increase in the level of WNK1 transcripts in leukocytes relative to those of their unaffected relatives, thus demonstrating that the deletion alters WNK1 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10869238+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><strong><em>Hereditary Sensory and Autonomic Neuropathy II</em></strong></p><p>
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Among from 5 families with HSAN2, including 2 from Newfoundland, 2 from rural Quebec, and 2 from Nova Scotia, <a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> identified 3 different truncating mutations in the WNK1 gene (594delA, <a href="#0003">605232.0003</a>; 918insA, <a href="#0004">605232.0004</a>; Q315X, <a href="#0005">605232.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060842" 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="#15" class="mim-tip-reference" title="Roddier, K., Thomas, T., Marleau, G., Gagnon, A. M., Dicaire, M. J., St-Denis, A., Gosselin, I., Sarrazin, A. M., Larbrisseau, A., Lambert, M., Vanasse, M., Gaudet, D., Rouleau, G. A., Brais, B. <strong>Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.</strong> Neurology 64: 1762-1767, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15911806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15911806</a>] [<a href="https://doi.org/10.1212/01.WNL.0000161849.29944.43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15911806">Roddier et al. (2005)</a> identified 2 founder mutations in the WNK1 gene (918insA and Q315X) that were responsible for HSAN2 in the southern part of Quebec. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15911806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Coen, K., Pareyson, D., Auer-Grumbach, M., Buyse, G., Goemans, N., Claeys, K. G., Verpoorten, N., Laura, M., Scaioli, V., Salmhofer, W., Pieber, T. R., Nelis, E., De Jonghe, P., Timmerman, V. <strong>Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.</strong> Neurology 66: 748-751, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16534117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16534117</a>] [<a href="https://doi.org/10.1212/01.wnl.0000201191.57519.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16534117">Coen et al. (2006)</a> reported 3 unrelated patients with HSAN2 from Italy, Austria, and Belgium, respectively. All had compound heterozygous or homozygous truncating mutations in the WNK1 gene, resulting in complete loss of protein function. All patients had early onset of a severe sensory neuropathy with mutilating acropathy but without autonomic dysfunction. Muscle strength was preserved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16534117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hypokalemic Salt-Losing Renal Tubulopathy</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Zhang, C., Zhu, Y., Huang, F., Jiang, G., Chang, J., Li, R. <strong>Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.</strong> Clin. Genet. 83: 545-552, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22934535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22934535</a>] [<a href="https://doi.org/10.1111/cge.12008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22934535">Zhang et al. (2013)</a> studied 44 Chinese patients with hypokalemia of unknown cause, metabolic alkalosis, and normal to low blood pressure. In 33 patients, they identified homozygosity or compound heterozygosity for known mutations in the CLCNKB (<a href="/entry/602023">602023</a>) or SLC12A3 (<a href="/entry/600968">600968</a>) genes, associated with forms of Bartter syndrome (see <a href="/entry/607364">607364</a>) and Gitelman syndrome (<a href="/entry/263800">263800</a>), respectively. Of the 11 remaining patients, 8 were heterozygous for a mutation in the SLC12A3 gene, whereas in 3, no mutation was detected in either gene. Screening for mutations in the candidate genes WNK1 and WNK4 (<a href="/entry/601844">601844</a>) revealed heterozygosity for 2 missense mutations in WNK1 (<a href="#0012">605232.0012</a> and <a href="#0013">605232.0013</a>, respectively) in 2 of the 11 patients, both of whom were also heterozygous for a known mutation in SLC12A3, each of which had previously been reported in a patient diagnosed with Gitelman syndrome (<a href="#18" class="mim-tip-reference" title="Simon, D. B., Nelson-Williams, C., Bia, M. J., Ellison, D., Karet, F. E., Molina, A. M., Vaara, I., Iwata, F., Cushner, H. M., Koolen, M., Gainza, F. J., Gitelman, H. J., Lifton, R. P. <strong>Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.</strong> Nature Genet. 12: 24-30, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528245</a>] [<a href="https://doi.org/10.1038/ng0196-24" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528245">Simon et al., 1996</a> and <a href="#16" class="mim-tip-reference" title="Shao, L., Liu, L., Miao, Z., Ren, H., Wang, W., Lang, Y., Yue, S., Chen, N. <strong>A novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney.</strong> Am. J. Nephrol. 28: 900-907, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18580052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18580052</a>] [<a href="https://doi.org/10.1159/000141932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18580052">Shao et al., 2008</a>, respectively). No mutations were detected in WNK4. <a href="#30" class="mim-tip-reference" title="Zhang, C., Zhu, Y., Huang, F., Jiang, G., Chang, J., Li, R. <strong>Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.</strong> Clin. Genet. 83: 545-552, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22934535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22934535</a>] [<a href="https://doi.org/10.1111/cge.12008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22934535">Zhang et al. (2013)</a> suggested that inactivating mutations in WNK1 may cause salt-losing renal tubulopathy, which represents a phenotype that is the converse of PHAII, caused by WNK1 gain-of-function mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22934535+18580052+8528245" 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 girl with HSAN2, <a href="#17" class="mim-tip-reference" title="Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A. <strong>Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.</strong> J. Clin. Invest. 118: 2496-2505, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18521183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18521183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18521183[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/JCI34088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18521183">Shekarabi et al. (2008)</a> identified compound heterozygosity for 2 mutations in the WNK1 gene: 1 in the WNK1/HSN2 isoform (<a href="#0010">605232.0010</a>) and 1 in the WNK1 isoform (<a href="#0011">605232.0011</a>). She did not have hypertension. The authors noted that all recessive mutations associated with the HSAN2 phenotype resulted in truncations of the WNK1/HSN2 nervous system-specific protein. Disease-causing mutations in WNK1 resulting in PHA2C were large, heterozygous intronic deletions that increase the gene expression. This impact on the expression level in PHA2C patients may explain the absence of hypertension in individuals affected with HSAN2, as the expression of the WNK1 isoform in which the HSN2 exon is not incorporated should not be affected. The findings in their patient suggested that 1 mutation in the HSN2 exon is sufficient to cause the HSAN2 phenotype when combined with a mutation in WNK1 on the other allele. Moreover, homozygous mutations disrupting WNK1 isoforms without HSN2 may be lethal, which would explain why all loss-of-function mutations reported to date have been located in the HSN2 exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18521183" 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>To accelerate the genetic determination of gene function, <a href="#29" class="mim-tip-reference" title="Zambrowicz, B. P., Abuin, A., Ramirez-Solis, R., Richter, L. J., Piggott, J., BeltrandelRio, H., Buxton, E. C., Edwards, J., Finch, R. A., Friddle, C. J., Gupta, A., Hansen, G., and 22 others. <strong>Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.</strong> Proc. Nat. Acad. Sci. 100: 14109-14114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14610273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14610273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14610273[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.2336103100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14610273">Zambrowicz et al. (2003)</a> developed a sequence-tagged gene-trap library of more than 270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, they undertook a functional screen to identify genes regulating physiologic parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 gene were generated and analyzed. Genetic studies in humans had shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II (<a href="#21" 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>), an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired potassium and hydrogen excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. <a href="#29" class="mim-tip-reference" title="Zambrowicz, B. P., Abuin, A., Ramirez-Solis, R., Richter, L. J., Piggott, J., BeltrandelRio, H., Buxton, E. C., Edwards, J., Finch, R. A., Friddle, C. J., Gupta, A., Hansen, G., and 22 others. <strong>Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.</strong> Proc. Nat. Acad. Sci. 100: 14109-14114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14610273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14610273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14610273[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.2336103100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14610273">Zambrowicz et al. (2003)</a> concluded that WNK1 is a regulator of blood pressure critical for development and illustrated the utility of a functional screen driven by a sequence-based mutagenesis approach. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11498583+14610273" 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 II (PHA2C; <a href="/entry/614492">614492</a>), <a href="#21" 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 41-kb deletion in intron 1 of the WNK1 gene. <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 II (PHA2C; <a href="/entry/614492">614492</a>) reported by <a href="#6" class="mim-tip-reference" title="Disse-Nicodeme, S., Achard, J.-M., Desitter, I., Houot, A.-M., Fournier, A., Corvol, P., Jeunemaitre, X. <strong>A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension.</strong> Am. J. Hum. Genet. 67: 302-310, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10869238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10869238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10869238[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/10.1086/303020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10869238">Disse-Nicodeme et al. (2000)</a>, <a href="#21" 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 21,761-bp deletion in intron 1 of the WNK1 gene. Affected individuals had a 5-fold increase in the level of WNK1 transcripts in leukocytes compared to those of unaffected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10869238+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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852734 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852734;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=rs137852734" 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=rs137852734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000020431 OR RCV001851969" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020431, RCV001851969" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020431...</a>
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<p>In affected members of 2 Newfoundland families with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), 1 of which was consanguineous, <a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> identified a homozygous 1-bp deletion in the HSN2 exon of the WNK1 gene, 594delA, resulting in a frameshift at codon 198 with a premature termination and a truncated 206-amino acid peptide. Numbering of this mutation is based on the HSN exon ORF only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060842" 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">rs137852735 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852735;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=rs137852735" 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=rs137852735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000020432 OR RCV000647840" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020432, RCV000647840" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020432...</a>
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<p>In 2 sisters from Nova Scotia, born to consanguineous parents, with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), <a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> found homozygosity for a 1-bp insertion in the HSN2 exon of the WNK1 gene, 918insA, resulting in a frameshift at codon 307 with a premature termination and a truncated 318-amino acid peptide. In 2 French Canadian sisters with HSAN2, the 918insA mutation was in compound heterozygous state with the Q315X mutation (<a href="#0005">605232.0005</a>). Numbering of this mutation is based on the HSN exon ORF only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060842" 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="#15" class="mim-tip-reference" title="Roddier, K., Thomas, T., Marleau, G., Gagnon, A. M., Dicaire, M. J., St-Denis, A., Gosselin, I., Sarrazin, A. M., Larbrisseau, A., Lambert, M., Vanasse, M., Gaudet, D., Rouleau, G. A., Brais, B. <strong>Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.</strong> Neurology 64: 1762-1767, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15911806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15911806</a>] [<a href="https://doi.org/10.1212/01.WNL.0000161849.29944.43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15911806">Roddier et al. (2005)</a> identified the 918insA mutation in 7 (58%) of 12 HSAN2 patients from the Lanaudiere region of southern Quebec, suggesting a founder effect. One patient was homozygous, and 6 were compound heterozygous with the Q315X mutation. Regional carrier frequency of the 918insA mutation was estimated to range from 1 in 260 to 1 in 28. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15911806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs111033590 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033590;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/rs111033590?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=rs111033590" 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=rs111033590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs111033591 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033591;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/rs111033591?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=rs111033591" 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=rs111033591" 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 French Canadian patient with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), <a href="#9" class="mim-tip-reference" title="Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others. <strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong> Am. J. Hum. Genet. 74: 1064-1073, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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/10.1086/420795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060842">Lafreniere et al. (2004)</a> found homozygosity for a 943C-T transition in the HSN2 exon of the WNK1 gene, resulting in a gln315-to-ter substitution (Q315X) predicted to truncate the protein to 314 amino acids. In 2 French Canadian sisters with HSAN2, the Q315X mutation was found in compound heterozygous state with the 918insA mutation (<a href="/entry/605343#0004">605343.0004</a>) in the HSN2 exon. Numbering of this mutation is based on the HSN exon ORF only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of families with HSAN2 from the southern part of Quebec, <a href="#15" class="mim-tip-reference" title="Roddier, K., Thomas, T., Marleau, G., Gagnon, A. M., Dicaire, M. J., St-Denis, A., Gosselin, I., Sarrazin, A. M., Larbrisseau, A., Lambert, M., Vanasse, M., Gaudet, D., Rouleau, G. A., Brais, B. <strong>Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.</strong> Neurology 64: 1762-1767, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15911806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15911806</a>] [<a href="https://doi.org/10.1212/01.WNL.0000161849.29944.43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15911806">Roddier et al. (2005)</a> identified the Q315X mutation. Nine (56%) of 16 patients were homozygous for the mutation, and 6 (38%) of 16 patients were compound heterozygous with the 918insA mutation. Most of the patients were from the Lanaudiere region. Regional carrier frequency of the Q315X mutation was estimated to range from 1 in 116 to 1 in 18. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15911806" 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">rs1951897077 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1951897077;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=rs1951897077" 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=rs1951897077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 affected members of a large consanguineous Lebanese family with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), <a href="#14" class="mim-tip-reference" title="Riviere, J.-B., Verlaan, D. J., Shekarabi, M., Lafreniere, R. G., Benard, M., Der Kaloustian, V. M., Shbaklo, Z., Rouleau, G. A. <strong>A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family.</strong> Ann. Neurol. 56: 572-575, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15455397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15455397</a>] [<a href="https://doi.org/10.1002/ana.20237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15455397">Riviere et al. (2004)</a> identified a homozygous 1-bp deletion (947delC) in the HSN2 exon of the WNK1 gene, resulting in the loss of 117 amino acids from the protein. Numbering of this mutation is based on the HSN exon ORF only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15455397" 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 13-year-old Canadian child of Lebanese origin with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), <a href="#15" class="mim-tip-reference" title="Roddier, K., Thomas, T., Marleau, G., Gagnon, A. M., Dicaire, M. J., St-Denis, A., Gosselin, I., Sarrazin, A. M., Larbrisseau, A., Lambert, M., Vanasse, M., Gaudet, D., Rouleau, G. A., Brais, B. <strong>Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.</strong> Neurology 64: 1762-1767, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15911806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15911806</a>] [<a href="https://doi.org/10.1212/01.WNL.0000161849.29944.43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15911806">Roddier et al. (2005)</a> identified a homozygous 868C-T transition in the HSN2 exon of the WNK1 gene, resulting in an arg290-to-ter (R290X) substitution. The authors noted that this mutation differed from that reported in another Lebanese family (<a href="#0006">605232.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15911806" 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 28-year-old Korean man with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), <a href="#2" class="mim-tip-reference" title="Cho, H.-J., Kim, B. J., Suh, Y.-L., An, J.-Y., Ki, C.-S. <strong>Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2.</strong> J. Hum. Genet. 51: 905-908, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16946995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16946995</a>] [<a href="https://doi.org/10.1007/s10038-006-0033-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16946995">Cho et al. (2006)</a> identified compound heterozygosity for 2 mutations in the HSN2 exon of the WNK1 gene: a 1-bp insertion (1134insT) and a 217C-T transition, resulting in a gln73-to-ter (Q73X; <a href="#0009">605232.0009</a>) substitution. The patient had childhood onset of the disorder and amputation of both lower limbs and several fingers due to ulceration and infection. The patient's unaffected mother was heterozygous for the 1-bp insertion, and 3 unaffected sibs were heterozygous for the Q73X mutation. The father was deceased. Numbering of this mutation is based on the HSN exon ORF only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16946995" 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="#19" class="mim-tip-reference" title="Takagi, M., Ozawa, T., Hara, K., Naruse, S., Ishihara, T., Shimbo, J., Igarashi, S., Tanaka, K., Onodera, O., Nishizawa, M. <strong>New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2.</strong> Neurology 66: 1251-1252, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16636245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16636245</a>] [<a href="https://doi.org/10.1212/01.wnl.0000208415.90685.cd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16636245">Takagi et al. (2006)</a> identified homozygosity for the 1134insT mutation in a Japanese patient with HSAN2, born of consanguineous parents. The insertion results in frameshift and premature termination of the protein at residue 378. The patient noted that he felt no pain in his extremities during his teenage years. He had recurrent skin ulcers on his fingers and toes resulting in spontaneous or surgical amputation of several digit tips. Physical examination at age 39 years showed no autonomic involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16636245" 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">rs111033592 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033592;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=rs111033592" 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=rs111033592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the gln73-to-ter (Q73X) mutation in the WNK1 gene that was identified in compound heterozygous state in a patient with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>) by <a href="#2" class="mim-tip-reference" title="Cho, H.-J., Kim, B. J., Suh, Y.-L., An, J.-Y., Ki, C.-S. <strong>Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2.</strong> J. Hum. Genet. 51: 905-908, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16946995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16946995</a>] [<a href="https://doi.org/10.1007/s10038-006-0033-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16946995">Cho et al. (2006)</a>, see <a href="#0008">605232.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16946995" 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">rs387906331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906331;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=rs387906331" 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=rs387906331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 18-year-old French girl with hereditary sensory neuropathy type IIA (HSAN2A; <a href="/entry/201300">201300</a>), <a href="#17" class="mim-tip-reference" title="Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A. <strong>Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.</strong> J. Clin. Invest. 118: 2496-2505, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18521183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18521183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18521183[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/JCI34088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18521183">Shekarabi et al. (2008)</a> identified a heterozygous 1-bp deletion (639delA) in the HSN2 exon of the WNK1 gene, resulting in a frameshift and premature termination. Numbering of this mutation is based on the HSN exon ORF only. Her unaffected father and brother also carried this deletion in heterozygosity. The original screening of the rest of the WNK1/HSN2 isoform did not reveal any mutations. However, subsequent screening of the girl in other exons in the WNK1 gene revealed a heterozygous 2-bp deletion (1584_1585delAG; <a href="#0011">605232.0011</a>) in exon 6 of the WNK1 gene, which resulted in a frameshift at codon 531 and premature termination at codon 547 (Asp531fsTer547). This deletion was inherited from the unaffected mother. Neither the girl nor the mother showed signs of hypertension. The findings prompted <a href="#17" class="mim-tip-reference" title="Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A. <strong>Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.</strong> J. Clin. Invest. 118: 2496-2505, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18521183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18521183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18521183[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/JCI34088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18521183">Shekarabi et al. (2008)</a> to conclude that HSN2 is an alternative exon within WNK1 rather than an independent gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18521183" 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>For discussion of the 2-bp deletion (1584_1585delAG) in the WNK1 gene that was identified in compound heterozygous state in a patient with hereditary sensory neuropathy type II (HSAN2A; <a href="/entry/201300">201300</a>), see <a href="#17" class="mim-tip-reference" title="Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A. <strong>Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.</strong> J. Clin. Invest. 118: 2496-2505, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18521183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18521183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18521183[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/JCI34088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18521183">Shekarabi et al. (2008)</a> and <a href="#0010">605232.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18521183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs150532648 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150532648;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/rs150532648?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=rs150532648" 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=rs150532648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049257 OR RCV000404011 OR RCV000537850 OR RCV003352760" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049257, RCV000404011, RCV000537850, RCV003352760" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049257...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to hypokalemic salt-losing renal tubulopathy (see <a href="/entry/241150">241150</a>) has not been confirmed due to the presence of an additional heterozygous mutation in the SLC12A3 gene (<a href="/entry/600968">600968</a>).</p><p>In a Chinese patient who presented at 10 years of age with fatigue, numbness, enuresis, and nocturia and was found to have hypokalemia, metabolic alkalosis, and low to normal blood pressure and to be heterozygous for a known splice site mutation (7426del13ins12; <a href="#16" class="mim-tip-reference" title="Shao, L., Liu, L., Miao, Z., Ren, H., Wang, W., Lang, Y., Yue, S., Chen, N. <strong>A novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney.</strong> Am. J. Nephrol. 28: 900-907, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18580052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18580052</a>] [<a href="https://doi.org/10.1159/000141932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18580052">Shao et al., 2008</a>) in the SLC12A3 gene, <a href="#30" class="mim-tip-reference" title="Zhang, C., Zhu, Y., Huang, F., Jiang, G., Chang, J., Li, R. <strong>Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.</strong> Clin. Genet. 83: 545-552, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22934535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22934535</a>] [<a href="https://doi.org/10.1111/cge.12008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22934535">Zhang et al. (2013)</a> identified heterozygosity for an A-G transition in exon 16 of the WNK1 gene, resulting in an ile1172-to-met (I1172M) substitution at an evolutionarily conserved residue within a coiled-coil domain in the C terminus. The I1172M mutation arose de novo, as neither parent carried the WNK1 variant, and it was not found in 400 control alleles or reported in dbSNP or HGMD databases. However, his unaffected mother was heterozygous for the SLC12A3 indel splice site mutation. Functional analysis in HEK293 cells using the corresponding rat WNK1 mutation, I918M, showed reduced SLC12A3 protein membrane expression in vitro when cotransfected with WNK4, due to complete abolishment of the suppressive effect of WNK4-mediated inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22934535+18580052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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WNK1, SER2047ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509409 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509409;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=rs397509409" 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=rs397509409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049258" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049258" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049258</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to hypokalemic salt-losing renal tubulopathy (see <a href="/entry/241150">241150</a>) has not been confirmed due to the presence of an additional heterozygous mutation in the SLC12A3 gene (<a href="/entry/600968">600968</a>).</p><p>In a Chinese man who presented at age 26 years with fatigue and hypotonia and was found to have hypokalemia, metabolic alkalosis, and low to normal blood pressure and to be heterozygous for a known missense mutation (D486N; <a href="#18" class="mim-tip-reference" title="Simon, D. B., Nelson-Williams, C., Bia, M. J., Ellison, D., Karet, F. E., Molina, A. M., Vaara, I., Iwata, F., Cushner, H. M., Koolen, M., Gainza, F. J., Gitelman, H. J., Lifton, R. P. <strong>Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.</strong> Nature Genet. 12: 24-30, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528245</a>] [<a href="https://doi.org/10.1038/ng0196-24" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528245">Simon et al., 1996</a>) in the SLC12A3 gene, <a href="#30" class="mim-tip-reference" title="Zhang, C., Zhu, Y., Huang, F., Jiang, G., Chang, J., Li, R. <strong>Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.</strong> Clin. Genet. 83: 545-552, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22934535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22934535</a>] [<a href="https://doi.org/10.1111/cge.12008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22934535">Zhang et al. (2013)</a> identified heterozygosity for a G-A transition in exon 24 of the WNK1 gene, resulting in a ser2047-to-asn (S2047N) substitution at a highly conserved residue within a coiled-coil domain in the C terminus. The S2047N WNK1 mutation was inherited from his father, who also displayed hypokalemia, alkalosis, and hypotension; the WNK1 variant was not found in 400 control alleles or reported in dbSNP or HGMD databases. The affected father and the patient's asymptomatic 2-year-old daughter also carried the SLC12A3 mutation, which was not found in other asymptomatic family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22934535+8528245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</h4>
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<p />
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="1" class="mim-anchor"></a>
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<a id="Anselmo2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Anselmo, A. N., Earnest, S., Chen, W., Juang, Y.-C., Kim, S. C., Zhao, Y., Cobb, M. H.
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<strong>WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.</strong>
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Proc. Nat. Acad. Sci. 103: 10883-10888, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16832045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16832045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16832045[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=16832045" 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.0604607103" target="_blank">Full Text</a>]
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<a id="Cho2006" class="mim-anchor"></a>
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Cho, H.-J., Kim, B. J., Suh, Y.-L., An, J.-Y., Ki, C.-S.
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<strong>Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2.</strong>
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J. Hum. Genet. 51: 905-908, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16946995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16946995</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16946995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10038-006-0033-1" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Choate2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Choate, K. A., Kahle, K. T., Wilson, F. H., Nelson-Williams, C., Lifton, R. P.
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<strong>WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl(-)-transporting epithelia.</strong>
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Proc. Nat. Acad. Sci. 100: 663-668, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12522152[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=12522152" 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.242728499" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Coen2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Coen, K., Pareyson, D., Auer-Grumbach, M., Buyse, G., Goemans, N., Claeys, K. G., Verpoorten, N., Laura, M., Scaioli, V., Salmhofer, W., Pieber, T. R., Nelis, E., De Jonghe, P., Timmerman, V.
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<strong>Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.</strong>
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Neurology 66: 748-751, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16534117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16534117</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16534117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000201191.57519.47" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Delaloy2003" class="mim-anchor"></a>
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Delaloy, C., Lu, J., Houot, A.-M., Disse-Nicodeme, S., Gasc, J.-M., Corvol, P., Jeunemaitre, X.
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<strong>Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.</strong>
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Molec. Cell. Biol. 23: 9208-9221, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645531</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14645531[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=14645531" 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/10.1128/MCB.23.24.9208-9221.2003" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Disse-Nicodeme2000" class="mim-anchor"></a>
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<div class="">
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Disse-Nicodeme, S., Achard, J.-M., Desitter, I., Houot, A.-M., Fournier, A., Corvol, P., Jeunemaitre, X.
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<strong>A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension.</strong>
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Am. J. Hum. Genet. 67: 302-310, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10869238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10869238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10869238[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=10869238" 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/10.1086/303020" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Gross2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 10/19/2016.
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<a id="8" class="mim-anchor"></a>
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<a id="He2007" class="mim-anchor"></a>
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<div class="">
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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: <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="9" class="mim-anchor"></a>
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<a id="Lafreniere2004" class="mim-anchor"></a>
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Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others.
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<strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong>
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Am. J. Hum. Genet. 74: 1064-1073, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15060842[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=15060842" 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/10.1086/420795" target="_blank">Full Text</a>]
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<a id="Lee2004" class="mim-anchor"></a>
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Lee, B.-H., Min, X., Heise, C. J., Xu, B., Chen, S., Shu, H., Luby-Phelps, K., Goldsmith, E. J., Cobb, M. H.
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<strong>WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding.</strong>
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Molec. Cell 15: 741-751, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15350218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15350218</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15350218" 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.molcel.2004.07.018" target="_blank">Full Text</a>]
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<a id="Lenertz2005" class="mim-anchor"></a>
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<div class="">
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Lenertz, L. Y., Lee, B.-H., Min, X., Xu, B., Wedin, K., Earnest, S., Goldsmith, E. J., Cobb, M. H.
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<strong>Properties of WNK1 and implications for other family members.</strong>
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J. Biol. Chem. 280: 26653-26658, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15883153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15883153</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15883153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M502598200" target="_blank">Full Text</a>]
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<a id="Moore2000" class="mim-anchor"></a>
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Moore, T. M., Garg, R., Johnson, C., Coptcoat, M. J., Ridley, A. J., Morris, J. D. H.
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<strong>PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization.</strong>
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J. Biol. Chem. 275: 4311-4322, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10660600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10660600</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10660600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.WNL.0000161849.29944.43" target="_blank">Full Text</a>]
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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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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Zambrowicz2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zambrowicz, B. P., Abuin, A., Ramirez-Solis, R., Richter, L. J., Piggott, J., BeltrandelRio, H., Buxton, E. C., Edwards, J., Finch, R. A., Friddle, C. J., Gupta, A., Hansen, G., and 22 others.
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<strong>Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.</strong>
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Proc. Nat. Acad. Sci. 100: 14109-14114, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14610273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14610273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14610273[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=14610273" 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.2336103100" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Zhang2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, C., Zhu, Y., Huang, F., Jiang, G., Chang, J., Li, R.
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<strong>Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.</strong>
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Clin. Genet. 83: 545-552, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22934535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22934535</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22934535" 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/10.1111/cge.12008" target="_blank">Full Text</a>]
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</p>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 10/19/2016
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 7/3/2013<br>Cassandra L. Kniffin - updated : 1/23/2009<br>Matthew B. Gross - updated : 2/5/2008<br>Patricia A. Hartz - updated : 1/17/2008<br>Patricia A. Hartz - updated : 10/18/2007<br>Patricia A. Hartz - updated : 10/5/2006<br>Patricia A. Hartz - updated : 9/1/2006<br>Patricia A. Hartz - updated : 7/11/2006<br>Patricia A. Hartz - updated : 5/11/2006<br>Marla J. F. O'Neill - updated : 5/20/2005<br>Victor A. McKusick - updated : 12/3/2004<br>Victor A. McKusick - updated : 4/23/2004<br>Victor A. McKusick - updated : 2/12/2003<br>Ada Hamosh - updated : 8/28/2001<br>Ada Hamosh - updated : 8/14/2001
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/28/2000
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/25/2024
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<span class="mim-text-font">
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carol : 11/26/2019<br>carol : 04/27/2018<br>mgross : 10/19/2016<br>carol : 10/18/2016<br>carol : 09/16/2013<br>carol : 7/3/2013<br>joanna : 4/25/2013<br>alopez : 2/27/2012<br>alopez : 2/27/2012<br>wwang : 2/6/2009<br>ckniffin : 1/23/2009<br>mgross : 2/5/2008<br>mgross : 2/5/2008<br>terry : 1/17/2008<br>mgross : 10/18/2007<br>terry : 10/18/2007<br>mgross : 10/5/2006<br>mgross : 9/6/2006<br>mgross : 9/1/2006<br>mgross : 7/11/2006<br>terry : 7/11/2006<br>wwang : 6/16/2006<br>wwang : 6/15/2006<br>terry : 5/11/2006<br>carol : 5/26/2005<br>terry : 5/20/2005<br>tkritzer : 12/8/2004<br>tkritzer : 12/7/2004<br>terry : 12/3/2004<br>tkritzer : 4/28/2004<br>terry : 4/23/2004<br>carol : 3/17/2004<br>mgross : 2/21/2003<br>terry : 2/12/2003<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 : 8/28/2000
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605232
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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PROSTATE-DERIVED STERILE 20-LIKE KINASE; PSK<br />
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PRKWNK1<br />
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KDP<br />
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KIAA0344
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</span>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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<span class="h3 mim-font">
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WNK1/HSN2 ISOFORM, INCLUDED
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: WNK1</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 860809000;
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<strong>
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<em>
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Cytogenetic location: 12p13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:752,579-911,452 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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12p13.33
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<td>
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<span class="mim-font">
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Neuropathy, hereditary sensory and autonomic, type II
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</td>
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<td>
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<span class="mim-font">
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201300
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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Pseudohypoaldosteronism, type IIC
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</span>
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</td>
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<td>
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<span class="mim-font">
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614492
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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<span class="mim-text-font">
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<p>Nagase et al. (1997) cloned a WNK1 cDNA, which they called KIAA0344. The deduced protein contains 1,246 amino acids. RT-PCR detected highest expression in kidney. </p><p>Using degenerate PCR against conserved kinase catalytic subdomains, Moore et al. (2000) cloned human WNK1, which they called PSK. PSK belongs to the STE20 family of serine-threonine kinases. The PSK protein contains 1,235 amino acids and has an N-terminal kinase domain. PSK was ubiquitously expressed in all tissues examined by Northern blot analysis, with strongest expression in testis. </p><p>Xu et al. (2000) isolated a full-length rat cDNA encoding Wnk1 and identified homologs in various species, including partial human sequences. The N-terminal half of the deduced 2,126-amino acid rat protein has a proline-rich region, followed by a serine/threonine kinase domain and coiled-coil region, and the C-terminal half has a proline-rich region and coiled-coil region. Wnk1 contains a cysteine instead of the usual lysine at a key position in its active site. Immunoblot analysis detected an endogenous 230-kD protein in rat brain and several mammalian cell lines, including human embryonic kidney (HEK293) cells. Most endogenous WNK1 protein was found in the particulate fraction of HEK293 cells, suggesting that WNK1 is associated with membranes or the cytoskeleton. Immunofluorescence analysis of HEK293 cells transfected with rat Wnk1 revealed cytoplasmic staining. </p><p>Wilson et al. (2001) noted that the deduced human and rat WNK1 proteins share 86% identity. By Northern blot analysis, they observed expression of human WNK1 in most tissues, with 2 predominant isoforms: a 10-kb transcript expressed at high levels in the kidney, and a 12-kb transcript predominant in heart and skeletal muscle. By immunofluorescence microscopy, Wilson et al. (2001) demonstrated that WNK1 localizes to the distal convoluted tubule and the cortical collecting duct, and is also abundant in the medullary collecting duct. </p><p>Choate et al. (2003) examined the distribution of WNK1 in extrarenal tissues. Immunostaining using WNK1-specific antibodies demonstrated that WNK1 was not present in all cell types; rather, it was predominantly localized in polarized epithelia, including those lining the lumen of the hepatic biliary ducts, pancreatic ducts, epididymis, sweat ducts, colonic crypts, and gallbladder. WNK1 was also found in the basal layers of epidermis and throughout the esophageal epithelium. Subcellular localization of WNK1 varied among these epithelia. WNK1 was cytoplasmic in kidney, colon, gallbladder, sweat duct, skin, and esophagus. In contrast, it localized to the lateral membrane in bile ducts, pancreatic ducts, and epididymis. These epithelia are all notable for their prominent role in chloride-iron flux. </p><p>Using primer extension with human leukocyte and kidney RNA, 5-prime RACE of human heart and kidney cDNA libraries, and RT-PCR of human heart, skeletal muscle, and kidney RNA, Delaloy et al. (2003) characterized several WNK1 variants resulting from tissue-specific splicing and the use of multiple transcriptional start sites and polyadenylation sites. Two promoters in exon 1 generate 2 ubiquitously expressed WNK1 isoforms with complete kinase domains. A third promoter in exon 4A generates a kidney-specific transcript that encodes an N-terminally truncated protein that is kinase defective. Exon 4A is highly conserved between human and rodents and encodes a cysteine-rich region. Northern blot analysis detected a 9-kb transcript expressed predominantly in human kidney and a 10.5-kb transcript expressed predominantly in skeletal muscle, heart, and brain. Qualitative RT-PCR detected 10 times more kinase-defective transcript than kinase domain-containing transcript in human kidney mRNA. In situ hybridization of adult mouse kidney using an exon 4A-specific probe revealed expression in kidney cortex, predominantly in distal convoluted tubules. </p><p><strong><em>WNK1/HSN2 Isoform</em></strong></p><p>
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Lafreniere et al. (2004) identified a novel gene, which they designated HSN2, within the hereditary sensory neuropathy type II (HSAN2; 201300) critical region on 12p13.33. The HSN2 gene encodes a deduced 434-amino acid protein. Northern blot analysis of adult human tissues failed to detect HSN2 transcripts, suggesting that the gene might be expressed at very low levels. Lafreniere et al. (2004) suggested that the HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells. </p><p>By Northern blot and RT-PCR analysis using mouse Wnk1, Shekarabi et al. (2008) concluded that HSN2 is an alternatively spliced exon of WNK1 and is part of a nervous system-specific isoform of WNK1, which they called WNK1/HSN2. Northern blot analysis of mouse tissues showed a 10-kb transcript exclusively expressed in nervous system tissues, including the spinal cord, brain, and dorsal root ganglia. RT-PCR analysis demonstrated that the Wnk1/Hsn2 isoform includes either the Hsn2 exon alone or Hsn2 along with a novel exon 8B and lacks exons 11 and 12. Immunohistochemical studies confirmed localization of the Wnk1/Hsn2 isoform to mouse nervous system tissues. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wilson et al. (2001) determined that the WNK1 gene contains 28 exons that span 156 kb of genomic DNA. </p><p>Delaloy et al. (2003) identified 2 promoters in exon 1 of the WNK1 gene, including 1 within the coding region, that generate ubiquitously expressed WNK1 transcripts. A third promoter, located in the alternative exon 4A within intron 4, generates a kidney-specific transcript. The promoters lack TATA boxes, are GC-rich, and contain several transcription factor-binding sites. A repressor element is present in the most 5-prime promoter in exon 1. In addition, WNK1 has multiple transcription start sites in exon 1 and 2 polyadenylation sites at its 3-prime end. </p><p><strong><em>WNK1/HSN2 Isoform</em></strong></p><p>
|
|
Lafreniere et al. (2004) determined that the HSN2 gene consists of a single exon that is located within intron 8 of the WNK1 gene and transcribed from the same strand. The authors initially concluded that the WNK1 and HSN2 genes were differentially regulated. Subsequently, Shekarabi et al. (2008) determined that HSN2 is a nervous-system specific exon of the WNK1 gene, and they identified a novel exon 8B. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By analysis of a radiation hybrid panel, Nagase et al. (1997) mapped the WNK1 gene to chromosome 12. </p><p>Gross (2016) mapped the WNK1 gene to chromosome 12p13.33 based on an alignment of the WNK1 sequence (GenBank AJ296290) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Moore et al. (2000) found that immunoprecipitated PSK phosphorylated myelin basic protein (159430) and transfected PSK-stimulated MKK4 (601335) and MKK7 (603014), and activated the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway (see 603014). Microinjection of PSK into cells resulted in localization of PSK to a vesicular compartment and caused a marked reduction in actin stress fibers. In contrast, C-terminally truncated PSK did not localize to this compartment or induce a decrease in stress fibers, demonstrating a requirement for the C terminus. Kinase-defective PSK, carrying a lys57-to-ala (K57A) mutation, was unable to reduce stress fibers. </p><p>Xu et al. (2002) expressed fragments of rat Wnk1 in bacteria and identified an autoinhibitory region just C-terminal to the kinase domain. The isolated autoinhibitory domain, which is conserved in all 4 human WNKs, suppressed the activity of the Wnk1 kinase domain. Mutation of 2 conserved phenylalanines in the autoinhibitory domain (phe524 and phe526 in rat Wnk1) attenuated its ability to inhibit Wnk1 kinase activity, and the same mutations in a Wnk1 fragment containing the autoinhibitory domain increased its kinase activity. Wnk1 expressed in bacteria was autophosphorylated, and autophosphorylation of ser382 in the activation loop was required for its activity. </p><p>Yang et al. (2003) found that mouse Wnk4 (601844) reduced the plasma membrane association of the thiazide-sensitive sodium-chloride cotransporter (NCC, or SLC12A3; 600968) in injected Xenopus oocytes. They further demonstrated that Wnk1 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 C 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>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. </p><p>Lee et al. (2004) found that rat Wnk1 selectively bound to and phosphorylated synaptotagmin-2 (SYT2; 600104) calcium-binding C2 domains. Endogenous Wnk1 and Syt2 coimmunoprecipitated and colocalized on a subset of secretory granules in a rat insulinoma cell line. Phosphorylation by Wnk1 increased the amount of Ca(2+) required for Syt2 binding to phospholipid vesicles. Lee et al. (2004) concluded that phosphorylation of SYT2 by WNK1 can regulate Ca(2+) sensing and the subsequent Ca(2+)-dependent interactions mediated by synaptotagmin C2 domains. </p><p>Lenertz et al. (2005) found that hypertonic stress activated rat Wnk1 when it was expressed in kidney epithelial cells and breast and colon cancer cell lines. Hypotonic stress led to a modest increase in Wnk1 activity. Gel filtration suggested that Wnk1 exists as a tetramer, and yeast 2-hybrid analysis revealed interaction between residues 1 to 222 of the Wnk1 N terminus and Wnk1 residues 481 to 660, which contain the autoinhibitory domain and a coiled-coil region. Lenertz et al. (2005) found no direct interaction between Wnk1 and Wnk4, but Wnk1 phosphorylated both Wnk2 (606249) and Wnk4, and the Wnk1 autoinhibitory domain inhibited the catalytic activities of Wnk2 and Wnk4. </p><p>Using Xenopus oocytes and Chinese hamster ovary cells, Xu et al. (2005) showed that WNK1 controls ion permeability by activating SGK1 (602958), leading to activation of the epithelial sodium channel (see SCNN1A; 600228). Increased WNK1-induced channel activity depended on SGK1 and the E3 ubiquitin ligase, NEDD4-2 (NEDD4L; 606384). </p><p>Alternative splicing of WNK1 produces a kidney-specific short form that lacks a kinase domain, KS-WNK1, and a more ubiquitous long form, L-WNK1. Using reconstitution studies in Xenopus oocytes, Wade et al. (2006) found that rat L-Wnk1 inhibited the K+ channel Kir1.1 (KCNJ1; 600359) by reducing its cell surface localization, and this inhibition required an intact kinase domain. Ks-Wnk1 did not directly alter Kir1.1 channel activity, but it acted as a dominant-negative inhibitor of L-Wnk1 and released Kir1.1 from inhibition. Acute dietary potassium loading in rats increased the relative abundance of Ks-Wnk1 to L-Wnk1 transcript and protein in kidney, indicating that physiologic upregulation of Kir1.1 activity involves a WNK1 isoform switch. </p><p>By yeast 2-hybrid analysis of Jurkat human T cells and immunoprecipitation analysis of human embryonic kidney cells and HeLa cells, Anselmo et al. (2006) showed that OSR1 (OXSR1; 604046) and WNK1 interacted through conserved C-terminal motifs. OSR1 was phosphorylated in a WNK1-dependent manner, and depletion of WNK1 from HeLa cells with small interfering RNA reduced OSR1 kinase activity. Depletion of either WNK1 or OSR1 reduced Na-K-Cl cotransporter (NKCC; see 600839) activity, suggesting that WNK1 and OSR1 are required for NKCC function. </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 (KCNJ1) endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4 required their proline-rich motifs, but it did not require their kinase activities. Pseudohypoaldosteronism II (145260)-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. </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><strong><em>Pseudohypoaldosteronism Type IIC</em></strong></p><p>
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Wilson et al. (2001) identified WNK1 as the gene mutant in one form of pseudohypoaldosteronism type II (PHA2C; 614492), an autosomal dominant disorder characterized by hypertension, hyperkalemia, and renal tubular acidosis. In a 10-member kindred segregating PHAII, they identified a 41-kb deletion in intron 1 of WNK1 (605232.0001). In the family previously described by Disse-Nicodeme et al. (2000), they identified a 22-kb deletion within intron 1 of WNK1 (605232.0002). Wilson et al. (2001) found that affected individuals carrying the 22-kb deletion had a 5-fold increase in the level of WNK1 transcripts in leukocytes relative to those of their unaffected relatives, thus demonstrating that the deletion alters WNK1 expression. </p><p><strong><em>Hereditary Sensory and Autonomic Neuropathy II</em></strong></p><p>
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Among from 5 families with HSAN2, including 2 from Newfoundland, 2 from rural Quebec, and 2 from Nova Scotia, Lafreniere et al. (2004) identified 3 different truncating mutations in the WNK1 gene (594delA, 605232.0003; 918insA, 605232.0004; Q315X, 605232.0005). </p><p>Roddier et al. (2005) identified 2 founder mutations in the WNK1 gene (918insA and Q315X) that were responsible for HSAN2 in the southern part of Quebec. </p><p>Coen et al. (2006) reported 3 unrelated patients with HSAN2 from Italy, Austria, and Belgium, respectively. All had compound heterozygous or homozygous truncating mutations in the WNK1 gene, resulting in complete loss of protein function. All patients had early onset of a severe sensory neuropathy with mutilating acropathy but without autonomic dysfunction. Muscle strength was preserved. </p><p><strong><em>Hypokalemic Salt-Losing Renal Tubulopathy</em></strong></p><p>
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Zhang et al. (2013) studied 44 Chinese patients with hypokalemia of unknown cause, metabolic alkalosis, and normal to low blood pressure. In 33 patients, they identified homozygosity or compound heterozygosity for known mutations in the CLCNKB (602023) or SLC12A3 (600968) genes, associated with forms of Bartter syndrome (see 607364) and Gitelman syndrome (263800), respectively. Of the 11 remaining patients, 8 were heterozygous for a mutation in the SLC12A3 gene, whereas in 3, no mutation was detected in either gene. Screening for mutations in the candidate genes WNK1 and WNK4 (601844) revealed heterozygosity for 2 missense mutations in WNK1 (605232.0012 and 605232.0013, respectively) in 2 of the 11 patients, both of whom were also heterozygous for a known mutation in SLC12A3, each of which had previously been reported in a patient diagnosed with Gitelman syndrome (Simon et al., 1996 and Shao et al., 2008, respectively). No mutations were detected in WNK4. Zhang et al. (2013) suggested that inactivating mutations in WNK1 may cause salt-losing renal tubulopathy, which represents a phenotype that is the converse of PHAII, caused by WNK1 gain-of-function mutations. </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>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a girl with HSAN2, Shekarabi et al. (2008) identified compound heterozygosity for 2 mutations in the WNK1 gene: 1 in the WNK1/HSN2 isoform (605232.0010) and 1 in the WNK1 isoform (605232.0011). She did not have hypertension. The authors noted that all recessive mutations associated with the HSAN2 phenotype resulted in truncations of the WNK1/HSN2 nervous system-specific protein. Disease-causing mutations in WNK1 resulting in PHA2C were large, heterozygous intronic deletions that increase the gene expression. This impact on the expression level in PHA2C patients may explain the absence of hypertension in individuals affected with HSAN2, as the expression of the WNK1 isoform in which the HSN2 exon is not incorporated should not be affected. The findings in their patient suggested that 1 mutation in the HSN2 exon is sufficient to cause the HSAN2 phenotype when combined with a mutation in WNK1 on the other allele. Moreover, homozygous mutations disrupting WNK1 isoforms without HSN2 may be lethal, which would explain why all loss-of-function mutations reported to date have been located in the HSN2 exon. </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>To accelerate the genetic determination of gene function, Zambrowicz et al. (2003) developed a sequence-tagged gene-trap library of more than 270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, they undertook a functional screen to identify genes regulating physiologic parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 gene were generated and analyzed. Genetic studies in humans had shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II (Wilson et al., 2001), an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired potassium and hydrogen excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. Zambrowicz et al. (2003) concluded that WNK1 is a regulator of blood pressure critical for development and illustrated the utility of a functional screen driven by a sequence-based mutagenesis approach. </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>13 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 IIC</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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WNK1, 41-KB DEL, IVS1
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<br />
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ClinVar: RCV000005468
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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 II (PHA2C; 614492), Wilson et al. (2001) identified a 41-kb deletion in intron 1 of the WNK1 gene. </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 IIC</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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WNK1, 22-KB DEL, IVS1
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<br />
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ClinVar: RCV000005469
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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 II (PHA2C; 614492) reported by Disse-Nicodeme et al. (2000), Wilson et al. (2001) identified a 21,761-bp deletion in intron 1 of the WNK1 gene. Affected individuals had a 5-fold increase in the level of WNK1 transcripts in leukocytes compared to those of unaffected family members. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, 1-BP DEL, 594A
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<br />
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SNP: rs137852734,
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ClinVar: RCV000020431, RCV001851969
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of 2 Newfoundland families with hereditary sensory neuropathy type II (HSAN2A; 201300), 1 of which was consanguineous, Lafreniere et al. (2004) identified a homozygous 1-bp deletion in the HSN2 exon of the WNK1 gene, 594delA, resulting in a frameshift at codon 198 with a premature termination and a truncated 206-amino acid peptide. Numbering of this mutation is based on the HSN exon ORF only. </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 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, 1-BP INS, 918A
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<br />
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SNP: rs137852735,
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ClinVar: RCV000020432, RCV000647840
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 sisters from Nova Scotia, born to consanguineous parents, with hereditary sensory neuropathy type II (HSAN2A; 201300), Lafreniere et al. (2004) found homozygosity for a 1-bp insertion in the HSN2 exon of the WNK1 gene, 918insA, resulting in a frameshift at codon 307 with a premature termination and a truncated 318-amino acid peptide. In 2 French Canadian sisters with HSAN2, the 918insA mutation was in compound heterozygous state with the Q315X mutation (605232.0005). Numbering of this mutation is based on the HSN exon ORF only. </p><p>Roddier et al. (2005) identified the 918insA mutation in 7 (58%) of 12 HSAN2 patients from the Lanaudiere region of southern Quebec, suggesting a founder effect. One patient was homozygous, and 6 were compound heterozygous with the Q315X mutation. Regional carrier frequency of the 918insA mutation was estimated to range from 1 in 260 to 1 in 28. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, GLN315TER
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<br />
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SNP: rs111033590, rs111033591,
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gnomAD: rs111033590, rs111033591,
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ClinVar: RCV000020433, RCV002321473
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a French Canadian patient with hereditary sensory neuropathy type II (HSAN2A; 201300), Lafreniere et al. (2004) found homozygosity for a 943C-T transition in the HSN2 exon of the WNK1 gene, resulting in a gln315-to-ter substitution (Q315X) predicted to truncate the protein to 314 amino acids. In 2 French Canadian sisters with HSAN2, the Q315X mutation was found in compound heterozygous state with the 918insA mutation (605343.0004) in the HSN2 exon. Numbering of this mutation is based on the HSN exon ORF only. </p><p>In affected members of families with HSAN2 from the southern part of Quebec, Roddier et al. (2005) identified the Q315X mutation. Nine (56%) of 16 patients were homozygous for the mutation, and 6 (38%) of 16 patients were compound heterozygous with the 918insA mutation. Most of the patients were from the Lanaudiere region. Regional carrier frequency of the Q315X mutation was estimated to range from 1 in 116 to 1 in 18. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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WNK1, 1-BP DEL, 947C
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<br />
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SNP: rs1951897077,
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ClinVar: RCV001249543
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected members of a large consanguineous Lebanese family with hereditary sensory neuropathy type II (HSAN2A; 201300), Riviere et al. (2004) identified a homozygous 1-bp deletion (947delC) in the HSN2 exon of the WNK1 gene, resulting in the loss of 117 amino acids from the protein. Numbering of this mutation is based on the HSN exon ORF only. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, ARG290TER
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<br />
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|
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SNP: rs111033591, rs111033592,
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gnomAD: rs111033591,
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ClinVar: RCV000005475, RCV000480631, RCV000822434
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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 13-year-old Canadian child of Lebanese origin with hereditary sensory neuropathy type II (HSAN2A; 201300), Roddier et al. (2005) identified a homozygous 868C-T transition in the HSN2 exon of the WNK1 gene, resulting in an arg290-to-ter (R290X) substitution. The authors noted that this mutation differed from that reported in another Lebanese family (605232.0006). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, 1-BP INS, 1134T
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<br />
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ClinVar: RCV000005476
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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 28-year-old Korean man with hereditary sensory neuropathy type II (HSAN2A; 201300), Cho et al. (2006) identified compound heterozygosity for 2 mutations in the HSN2 exon of the WNK1 gene: a 1-bp insertion (1134insT) and a 217C-T transition, resulting in a gln73-to-ter (Q73X; 605232.0009) substitution. The patient had childhood onset of the disorder and amputation of both lower limbs and several fingers due to ulceration and infection. The patient's unaffected mother was heterozygous for the 1-bp insertion, and 3 unaffected sibs were heterozygous for the Q73X mutation. The father was deceased. Numbering of this mutation is based on the HSN exon ORF only. </p><p>Takagi et al. (2006) identified homozygosity for the 1134insT mutation in a Japanese patient with HSAN2, born of consanguineous parents. The insertion results in frameshift and premature termination of the protein at residue 378. The patient noted that he felt no pain in his extremities during his teenage years. He had recurrent skin ulcers on his fingers and toes resulting in spontaneous or surgical amputation of several digit tips. Physical examination at age 39 years showed no autonomic involvement. </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>.0009 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, GLN73TER
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<br />
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SNP: rs111033592,
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ClinVar: RCV000005471
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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>For discussion of the gln73-to-ter (Q73X) mutation in the WNK1 gene that was identified in compound heterozygous state in a patient with hereditary sensory neuropathy type II (HSAN2A; 201300) by Cho et al. (2006), see 605232.0008. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, 1-BP DEL, 639A
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<br />
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SNP: rs387906331,
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ClinVar: RCV000005477
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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 an 18-year-old French girl with hereditary sensory neuropathy type IIA (HSAN2A; 201300), Shekarabi et al. (2008) identified a heterozygous 1-bp deletion (639delA) in the HSN2 exon of the WNK1 gene, resulting in a frameshift and premature termination. Numbering of this mutation is based on the HSN exon ORF only. Her unaffected father and brother also carried this deletion in heterozygosity. The original screening of the rest of the WNK1/HSN2 isoform did not reveal any mutations. However, subsequent screening of the girl in other exons in the WNK1 gene revealed a heterozygous 2-bp deletion (1584_1585delAG; 605232.0011) in exon 6 of the WNK1 gene, which resulted in a frameshift at codon 531 and premature termination at codon 547 (Asp531fsTer547). This deletion was inherited from the unaffected mother. Neither the girl nor the mother showed signs of hypertension. The findings prompted Shekarabi et al. (2008) to conclude that HSN2 is an alternative exon within WNK1 rather than an independent gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 NEUROPATHY, HEREDITARY SENSORY, TYPE IIA</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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WNK1, 2-BP DEL, 1584AG
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<br />
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SNP: rs387906332,
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ClinVar: RCV000005478
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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>For discussion of the 2-bp deletion (1584_1585delAG) in the WNK1 gene that was identified in compound heterozygous state in a patient with hereditary sensory neuropathy type II (HSAN2A; 201300), see Shekarabi et al. (2008) and 605232.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0012 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WNK1, ILE1172MET
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<br />
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SNP: rs150532648,
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gnomAD: rs150532648,
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ClinVar: RCV000049257, RCV000404011, RCV000537850, RCV003352760
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to hypokalemic salt-losing renal tubulopathy (see 241150) has not been confirmed due to the presence of an additional heterozygous mutation in the SLC12A3 gene (600968).</p><p>In a Chinese patient who presented at 10 years of age with fatigue, numbness, enuresis, and nocturia and was found to have hypokalemia, metabolic alkalosis, and low to normal blood pressure and to be heterozygous for a known splice site mutation (7426del13ins12; Shao et al., 2008) in the SLC12A3 gene, Zhang et al. (2013) identified heterozygosity for an A-G transition in exon 16 of the WNK1 gene, resulting in an ile1172-to-met (I1172M) substitution at an evolutionarily conserved residue within a coiled-coil domain in the C terminus. The I1172M mutation arose de novo, as neither parent carried the WNK1 variant, and it was not found in 400 control alleles or reported in dbSNP or HGMD databases. However, his unaffected mother was heterozygous for the SLC12A3 indel splice site mutation. Functional analysis in HEK293 cells using the corresponding rat WNK1 mutation, I918M, showed reduced SLC12A3 protein membrane expression in vitro when cotransfected with WNK4, due to complete abolishment of the suppressive effect of WNK4-mediated inhibition. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
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<span class="mim-text-font">
|
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WNK1, SER2047ASN
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<br />
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|
|
SNP: rs397509409,
|
|
|
|
|
|
|
|
ClinVar: RCV000049258
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to hypokalemic salt-losing renal tubulopathy (see 241150) has not been confirmed due to the presence of an additional heterozygous mutation in the SLC12A3 gene (600968).</p><p>In a Chinese man who presented at age 26 years with fatigue and hypotonia and was found to have hypokalemia, metabolic alkalosis, and low to normal blood pressure and to be heterozygous for a known missense mutation (D486N; Simon et al., 1996) in the SLC12A3 gene, Zhang et al. (2013) identified heterozygosity for a G-A transition in exon 24 of the WNK1 gene, resulting in a ser2047-to-asn (S2047N) substitution at a highly conserved residue within a coiled-coil domain in the C terminus. The S2047N WNK1 mutation was inherited from his father, who also displayed hypokalemia, alkalosis, and hypotension; the WNK1 variant was not found in 400 control alleles or reported in dbSNP or HGMD databases. The affected father and the patient's asymptomatic 2-year-old daughter also carried the SLC12A3 mutation, which was not found in other asymptomatic family members. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Anselmo, A. N., Earnest, S., Chen, W., Juang, Y.-C., Kim, S. C., Zhao, Y., Cobb, M. H.
|
|
<strong>WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 10883-10888, 2006.
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[PubMed: 16832045]
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[Full Text: https://doi.org/10.1073/pnas.0604607103]
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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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Cho, H.-J., Kim, B. J., Suh, Y.-L., An, J.-Y., Ki, C.-S.
|
|
<strong>Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2.</strong>
|
|
J. Hum. Genet. 51: 905-908, 2006.
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[PubMed: 16946995]
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[Full Text: https://doi.org/10.1007/s10038-006-0033-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Choate, K. A., Kahle, K. T., Wilson, F. H., Nelson-Williams, C., Lifton, R. P.
|
|
<strong>WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl(-)-transporting epithelia.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 663-668, 2003.
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[PubMed: 12522152]
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[Full Text: https://doi.org/10.1073/pnas.242728499]
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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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Coen, K., Pareyson, D., Auer-Grumbach, M., Buyse, G., Goemans, N., Claeys, K. G., Verpoorten, N., Laura, M., Scaioli, V., Salmhofer, W., Pieber, T. R., Nelis, E., De Jonghe, P., Timmerman, V.
|
|
<strong>Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.</strong>
|
|
Neurology 66: 748-751, 2006.
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|
|
[PubMed: 16534117]
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[Full Text: https://doi.org/10.1212/01.wnl.0000201191.57519.47]
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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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Delaloy, C., Lu, J., Houot, A.-M., Disse-Nicodeme, S., Gasc, J.-M., Corvol, P., Jeunemaitre, X.
|
|
<strong>Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.</strong>
|
|
Molec. Cell. Biol. 23: 9208-9221, 2003.
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[PubMed: 14645531]
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[Full Text: https://doi.org/10.1128/MCB.23.24.9208-9221.2003]
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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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Disse-Nicodeme, S., Achard, J.-M., Desitter, I., Houot, A.-M., Fournier, A., Corvol, P., Jeunemaitre, X.
|
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<strong>A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension.</strong>
|
|
Am. J. Hum. Genet. 67: 302-310, 2000.
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[PubMed: 10869238]
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[Full Text: https://doi.org/10.1086/303020]
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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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Gross, M. B.
|
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 10/19/2016.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
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.
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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">
|
|
Lafreniere, R. G., MacDonald, M. L. E., Dube, M.-P., MacFarlane, J., O'Driscoll, M., Brais, B., Meilleur, S., Brinkman, R. R., Dadivas, O., Pape, T., Platon, C., Radomski, C., and 14 others.
|
|
<strong>Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates.</strong>
|
|
Am. J. Hum. Genet. 74: 1064-1073, 2004.
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|
|
[PubMed: 15060842]
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[Full Text: https://doi.org/10.1086/420795]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lee, B.-H., Min, X., Heise, C. J., Xu, B., Chen, S., Shu, H., Luby-Phelps, K., Goldsmith, E. J., Cobb, M. H.
|
|
<strong>WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding.</strong>
|
|
Molec. Cell 15: 741-751, 2004.
|
|
|
|
|
|
[PubMed: 15350218]
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|
|
[Full Text: https://doi.org/10.1016/j.molcel.2004.07.018]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lenertz, L. Y., Lee, B.-H., Min, X., Xu, B., Wedin, K., Earnest, S., Goldsmith, E. J., Cobb, M. H.
|
|
<strong>Properties of WNK1 and implications for other family members.</strong>
|
|
J. Biol. Chem. 280: 26653-26658, 2005.
|
|
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|
|
[PubMed: 15883153]
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|
|
[Full Text: https://doi.org/10.1074/jbc.M502598200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Moore, T. M., Garg, R., Johnson, C., Coptcoat, M. J., Ridley, A. J., Morris, J. D. H.
|
|
<strong>PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization.</strong>
|
|
J. Biol. Chem. 275: 4311-4322, 2000.
|
|
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|
|
[PubMed: 10660600]
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|
|
[Full Text: https://doi.org/10.1074/jbc.275.6.4311]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Nagase, T., Ishikawa, I., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., O'Hara, O.
|
|
<strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong>
|
|
DNA Res. 4: 141-150, 1997.
|
|
|
|
|
|
[PubMed: 9205841]
|
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|
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|
|
[Full Text: https://doi.org/10.1093/dnares/4.2.141]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Riviere, J.-B., Verlaan, D. J., Shekarabi, M., Lafreniere, R. G., Benard, M., Der Kaloustian, V. M., Shbaklo, Z., Rouleau, G. A.
|
|
<strong>A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family.</strong>
|
|
Ann. Neurol. 56: 572-575, 2004.
|
|
|
|
|
|
[PubMed: 15455397]
|
|
|
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|
|
[Full Text: https://doi.org/10.1002/ana.20237]
|
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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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<strong>Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.</strong>
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Shao, L., Liu, L., Miao, Z., Ren, H., Wang, W., Lang, Y., Yue, S., Chen, N.
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Shekarabi, M., Girard, N., Riviere, J.-B., Dion, P., Houle, M., Toulouse, A., Lafreniere, R. G., Vercauteren, F., Hince, P., Laganiere, J., Rochefort, D., Faivre, L., Samuels, M., Rouleau, G. A.
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<strong>Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.</strong>
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Takagi, M., Ozawa, T., Hara, K., Naruse, S., Ishihara, T., Shimbo, J., Igarashi, S., Tanaka, K., Onodera, O., Nishizawa, M.
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<strong>WNK1 kinase isoform switch regulates renal potassium excretion.</strong>
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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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Xu, B. E., Min, X., Stippec, S., Lee, B. H., Goldsmith, E. J., Cobb, M. H.
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<strong>Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.</strong>
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Xu, B., English, J. M., Wilsbacher, J. L., Stippec, S., Goldsmith, E. J., Cobb, M. H.
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<strong>WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.</strong>
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Xu, B., Stippec, S., Chu, P.-Y., Lazrak, A., Li, X.-J., Lee, B.-H., English, J. M., Ortega, B., Huang, C.-L., Cobb, M. H.
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<strong>WNK1 activates SGK1 to regulate the epithelial sodium channel.</strong>
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Proc. Nat. Acad. Sci. 102: 10315-10320, 2005.
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Yang, C.-L., Angell, J., Mitchell, R., Ellison, D. H.
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<strong>WNK kinases regulate thiazide-sensitive Na-Cl cotransport.</strong>
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J. Clin. Invest. 111: 1039-1045, 2003.
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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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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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J. Clin. Invest. 117: 3403-3411, 2007.
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[PubMed: 17975670]
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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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[PubMed: 15841204]
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Zambrowicz, B. P., Abuin, A., Ramirez-Solis, R., Richter, L. J., Piggott, J., BeltrandelRio, H., Buxton, E. C., Edwards, J., Finch, R. A., Friddle, C. J., Gupta, A., Hansen, G., and 22 others.
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<strong>Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.</strong>
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Proc. Nat. Acad. Sci. 100: 14109-14114, 2003.
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Zhang, C., Zhu, Y., Huang, F., Jiang, G., Chang, J., Li, R.
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<strong>Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.</strong>
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