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Entry
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- *300008 - CHLORIDE CHANNEL 5; CLCN5
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300008</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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="#biochemicalFeatures">Biochemical Features</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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</li>
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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>
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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/300008">Table View</a>
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</li>
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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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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000171365;t=ENST00000376091" 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=1184" 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=300008" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000171365;t=ENST00000376091" 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_000084,NM_001127898,NM_001127899,NM_001272102,NM_001282163,XM_017029257,XM_017029258,XM_047441807,XM_047441808" 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_001127898" 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=300008" 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=02053&isoform_id=02053_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/CLCN5" 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/577053,1171562,4557473,33438573,119610335,120659868,120660212,158255316,189217921,189217923,193786465,193787268,442535514,531990846,1034673474,1034673476,1890389180,2217390972,2217390974,2462628154,2462628156,2462628158" 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/P51795" 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=1184" 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=ENSG00000171365;t=ENST00000376091" 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=CLCN5" 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=CLCN5" 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+1184" 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/CLCN5" 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:1184" 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/1184" 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=chrX&hgg_gene=ENST00000376091.8&hgg_start=49922596&hgg_end=50099230&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/gene-dosage/HGNC:2023" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2023" 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/clcn5" 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=300008[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=300008[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/CLCN5/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/ENSG00000171365" 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=CLCN5" 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=CLCN5" 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=CLCN5" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/CLCN5" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CLCN5&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/PA26550" 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:2023" 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/FBgn0036566.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:99486" 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/CLCN5#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:99486" 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/1184/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=1184" 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=WBGene00000532;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-091113-15" 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:1184" 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=CLCN5&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> 444645005, 717789008<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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300008
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
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<span class="mim-font">
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CHLORIDE CHANNEL 5; CLCN5
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CHLORIDE CHANNEL, VOLTAGE-GATED, K2; CLCK2<br />
|
|
CLC5
|
|
</span>
|
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</h4>
|
|
</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CLCN5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CLCN5</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/293?start=-3&limit=10&highlight=293">Xp11.23</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:49922596-50099230&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'})">X:49,922,596-50,099,230</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300009,300554,310468,308990" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/293?start=-3&limit=10&highlight=293">
|
|
Xp11.23
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Dent disease 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300009"> 300009 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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<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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<p>The CLCN5 gene encodes a voltage-gated chloride ion channel that belongs to a distinct branch of the chloride channel (CLC) family, which also includes CLCN3 (<a href="/entry/600580">600580</a>) and CLCN4 (<a href="/entry/302910">302910</a>) (<a href="#12" class="mim-tip-reference" title="Fisher, S. E., Van Bakel, I., Lloyd, S. E., Pearce, S. H. S., Thakker, R. V., Craig, I. W. <strong>Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis).</strong> Genomics 29: 598-606, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575751</a>] [<a href="https://doi.org/10.1006/geno.1995.9960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575751">Fisher et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575751" 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 positional cloning of a microdeletion at chromosome Xp11.22 identified in a family with Dent disease (DENT1; <a href="/entry/300009">300009</a>), <a href="#11" class="mim-tip-reference" title="Fisher, S. E., Black, G. C. M., Lloyd, S. E., Hatchwell, E., Wrong, O., Thakker, R. V., Craig, I. W. <strong>Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis).</strong> Hum. Molec. Genet. 3: 2053-2059, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874126</a>]" pmid="7874126">Fisher et al. (1994)</a> isolated a coding sequence from a human kidney cDNA library. Sequence analysis suggested that CLCN5, which they termed CLCK2, encoded a new member of the CLC family of voltage-gated chloride channels. A 9.5-kb mRNA transcript was expressed predominantly in the kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Fisher, S. E., Van Bakel, I., Lloyd, S. E., Pearce, S. H. S., Thakker, R. V., Craig, I. W. <strong>Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis).</strong> Genomics 29: 598-606, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575751</a>] [<a href="https://doi.org/10.1006/geno.1995.9960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575751">Fisher et al. (1995)</a> described the isolation and characterization of the complete open reading frame of CLCN5, which encodes a deduced 746-amino acid protein with significant homology to all known members of the family of voltage-gated chloride channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575751" 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="#12" class="mim-tip-reference" title="Fisher, S. E., Van Bakel, I., Lloyd, S. E., Pearce, S. H. S., Thakker, R. V., Craig, I. W. <strong>Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis).</strong> Genomics 29: 598-606, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575751</a>] [<a href="https://doi.org/10.1006/geno.1995.9960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575751">Fisher et al. (1995)</a> determined that the CLCN5 gene contains 12 exons and spans 25 to 30 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575751" 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 positional cloning, <a href="#11" class="mim-tip-reference" title="Fisher, S. E., Black, G. C. M., Lloyd, S. E., Hatchwell, E., Wrong, O., Thakker, R. V., Craig, I. W. <strong>Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis).</strong> Hum. Molec. Genet. 3: 2053-2059, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874126</a>]" pmid="7874126">Fisher et al. (1994)</a> identified the CLCN5 gene within the minimum candidate region for Dent disease (DENT1; <a href="/entry/300009">300009</a>) on Xp11.22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874126" 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 the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, <a href="#3" class="mim-tip-reference" title="Blair, H. J., Ho, M., Monaco, A. P., Fisher, S., Craig, I. W., Boyd, Y. <strong>High-resolution comparative mapping of the proximal region of the mouse X chromosome.</strong> Genomics 28: 305-310, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530041</a>] [<a href="https://doi.org/10.1006/geno.1995.1146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530041">Blair et al. (1995)</a> demonstrated the location of the Clcn5 gene in relation to others. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8530041" 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="#10" class="mim-tip-reference" title="Dutzler, R., Campbell, E. B., Cadene, M., Chait, B. T., MacKinnon, R. <strong>X-ray structure of a ClC chloride channel at 3.0 angstrom reveals the molecular basis of anion selectivity.</strong> Nature 415: 287-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11796999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11796999</a>] [<a href="https://doi.org/10.1038/415287a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11796999">Dutzler et al. (2002)</a> presented the x-ray structures of 2 prokaryotic CLC chloride channels, from Salmonella typhimurium and E. coli, at 3.0 and 3.5 angstroms, respectively. Both structures revealed 2 identical pores, each pore being formed by a separate subunit contained within a homodimeric membrane protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11796999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Gunther, W., Luchow, A., Cluzeaud, F., Vandewalle, A., Jentsch, T. J. <strong>ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.</strong> Proc. Nat. Acad. Sci. 95: 8075-8080, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653142</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653142[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653142">Gunther et al. (1998)</a> showed that the CLCN5 gene was expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression was highest below the brush border in a region densely packed with endocytotic vesicles, where CLC5 colocalizes with the H(+)-ATPase and with internalized proteins early after uptake. CLCN5 localized to apical intracellular vesicles in intercalated cells of the collecting duct, and colocalized with the proton pump in alpha-intercalated cells. In transfected cells, CLC5 colocalized with endocytosed alpha-2-macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant led to enlarged early endosomes that stained for CLC5. <a href="#13" class="mim-tip-reference" title="Gunther, W., Luchow, A., Cluzeaud, F., Vandewalle, A., Jentsch, T. J. <strong>ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.</strong> Proc. Nat. Acad. Sci. 95: 8075-8080, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653142</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653142[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653142">Gunther et al. (1998)</a> suggested that CLC5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Devuyst, O., Christie, P. T., Courtoy, P. J., Beauwens, R., Thakker, R. V. <strong>Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease.</strong> Hum. Molec. Genet. 8: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931332</a>] [<a href="https://doi.org/10.1093/hmg/8.2.247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931332">Devuyst et al. (1999)</a> raised specific antisera against human CLC5 and identified by immunoblotting an 83-kD band corresponding to CLC5 in human kidney cortex and medulla. Immunohistochemistry revealed CLC5 expression in the epithelial cells lining the proximal tubules and the thick ascending limbs of the Henle loop, and in the intercalated cells of the collecting ducts. Subcellular fractionation studies of human kidney established that CLC5 distribution was most closely associated with that of Rab4, a marker of recycling early endosomes. Confocal microscopy using the proximal tubular cell model of opossum kidney cells, which endogenously express CLC5, revealed that CLC5 colocalized with the albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway. The expression of CLC5 at multiple sites in the kidney explained the proteinuria and hypercalciuria which characterize Dent disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931332" 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>As described by <a href="#19" class="mim-tip-reference" title="Novarino, G., Weinert, S., Rickheit, G., Jentsch, T. J. <strong>Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.</strong> Science 328: 1398-1401, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20430975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20430975</a>] [<a href="https://doi.org/10.1126/science.1188070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20430975">Novarino et al. (2010)</a>, CLC5 is a 2-chloride (Cl-)/proton (H+) exchanger rather than a chloride channel (see <a href="#21" class="mim-tip-reference" title="Picollo, A., Pusch, M. <strong>Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5.</strong> Nature 436: 420-423, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16034421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16034421</a>] [<a href="https://doi.org/10.1038/nature03720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16034421">Picollo and Pusch, 2005</a>, <a href="#23" class="mim-tip-reference" title="Scheel, O., Zdebik, A. A., Lourdel, S., Jentsch, T. J. <strong>Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins.</strong> Nature 436: 424-427, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16034422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16034422</a>] [<a href="https://doi.org/10.1038/nature03860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16034422">Scheel et al., 2005</a>, and <a href="#28" class="mim-tip-reference" title="Zifarelli, G., Pusch, G. <strong>Conversion of the 2 Cl-/1 H+ antiporter ClC-5 in a NO(3)-/H+ antiporter by a single point mutation.</strong> EMBO J. 28: 175-182, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19131966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19131966</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19131966[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/emboj.2008.284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19131966">Zifarelli and Pusch, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16034421+20430975+19131966+16034422" 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="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified 11 mutations in the CLCN5 gene in affected members of 8 kindreds with Dent disease-1 (<a href="/entry/300009">300009</a>) (see, e.g., <a href="#0001">300008.0001</a>-<a href="#0004">300008.0004</a>), 2 families with X-linked recessive nephrolithiasis (XRN; <a href="/entry/310468">310468</a>; <a href="#0005">300008.0005</a>-<a href="#0006">300008.0006</a>), and 1 family with X-linked recessive hypophosphatemic rickets (XLHRR; <a href="/entry/300554">300554</a>; <a href="#0007">300008.0007</a>). All 4 missense mutations were confined to the predicted transmembrane domains. In vitro functional expression studies showed that the mutations markedly reduced or abolished outwardly rectifying chloride currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" 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 from 4 unrelated Japanese kindreds with low molecular weight proteinuria (<a href="/entry/308990">308990</a>), <a href="#16" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V. <strong>Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).</strong> J. Clin. Invest. 99: 967-974, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9062355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9062355</a>] [<a href="https://doi.org/10.1172/JCI119262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9062355">Lloyd et al. (1997)</a> identified 4 different mutations in the CLCN5 gene (<a href="#0001">300008.0001</a>; <a href="#0008">300008.0008</a>-<a href="#0010">300008.0010</a>). <a href="#18" class="mim-tip-reference" title="Nakazato, H., Hattori, S., Furuse, A., Kawano, T., Karashima, S., Tsuruta, M., Yoshimuta, J., Endo, F., Matsuda, I. <strong>Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria.</strong> Kidney Int. 52: 895-900, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328927</a>] [<a href="https://doi.org/10.1038/ki.1997.410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328927">Nakazato et al. (1997)</a> identified mutations in the CLCN5 gene in affected members of 2 Japanese families with low molecular weight proteinuria. <a href="#1" class="mim-tip-reference" title="Akuta, N., Lloyd, S. E., Igarashi, T., Shiraga, H., Matsuyama, T., Yokoro, S., Cox, J. P. D., Thakker, R. V. <strong>Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis.</strong> Kidney Int. 52: 911-916, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328929</a>] [<a href="https://doi.org/10.1038/ki.1997.412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328929">Akuta et al. (1997)</a> identified mutations in the CLCN5 gene in 7 of 10 unrelated Japanese patients with low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. They estimated that over 70% of Japanese patients with the disorder have mutations in the CLCN5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9328929+9062355+9328927" 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 8 unrelated patients with Dent disease, <a href="#8" class="mim-tip-reference" title="Cox, J. P. D., Yamamoto, K., Christie, P. T., Wooding, C., Feest, T., Flinter, F. A., Goodyer, P. R., Leumann, E., Neuhaus, T., Reid, C., Williams, P. F., Wrong, O., Thakker, R. V. <strong>Renal chloride channel, CLCN5, mutations in Dent's disease.</strong> J. Bone Miner. Res. 14: 1536-1542, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10469281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10469281</a>] [<a href="https://doi.org/10.1359/jbmr.1999.14.9.1536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10469281">Cox et al. (1999)</a> found 3 nonsense mutations, 4 deletions of single codons, and 1 acceptor splice consensus sequence mutation in the CLCN5 gene. None of these mutations was found in a study of unrelated normal individuals. All of the mutations predicted truncated chloride channels that were likely to result in a functional loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10469281" 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>After heterologous expression of various mutant CLCN5 cDNAs in Xenopus oocytes, <a href="#17" class="mim-tip-reference" title="Ludwig, M., Doroszewicz, J., Seyberth, H. W., Bokenkamp, A., Balluch, B., Nuutinen, M., Utsch, B., Waldegger, S. <strong>Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization.</strong> Hum. Genet. 117: 228-237, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895257</a>] [<a href="https://doi.org/10.1007/s00439-005-1303-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895257">Ludwig et al. (2005)</a> observed that except for the R516W and R648X (<a href="#0002">300008.0002</a>) variants, none of the mutated proteins induced functional chloride currents or reached the plasma membrane. The tested missense mutations were distributed over different transmembrane regions, implying that correct channel structure and orientation in the membrane is not only a prerequisite for proper CLCN5 function but also for Golgi exit. The R648X mutant, although functionally compromised (30% of wildtype current), displayed a significant increase in surface expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15895257" 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="Tosetto, E., Ceol, M,, Mezzabotta, F., Ammenti, A., Peruzzi, L., Caruso, M. R., Barbano, G., Vezzoli, G., Colussi, G., Vergine, G., Giordano, M., Glorioso, N., Degortes, S., Soldati, L., Sayer, J., D'Angelo, A., Anglani, F. <strong>Novel mutations of the CLCN5 gene including a complex allele and a 5-prime UTR mutation in Dent disease 1. (Letter)</strong> Clin. Genet. 76: 413-416, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19673950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19673950</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01212.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19673950">Tosetto et al. (2009)</a> identified mutations in the CLCN5 gene, including 15 novel mutations (see, e.g., <a href="#0014">300008.0014</a>), in 16 (53%) of 30 mostly Italian patients with a clinical suspicion of Dent disease. Most of the missense mutations were predicted to occur in the helix regions involved in the CLCN5 dimer interface. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19673950" 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="#22" class="mim-tip-reference" title="Piwon, N., Gunther, W., Schwake, M., Bosl, M. R., Jentsch, T. J. <strong>ClC-5 Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease.</strong> Nature 408: 369-373, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11099045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11099045</a>] [<a href="https://doi.org/10.1038/35042597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11099045">Piwon et al. (2000)</a> created a mouse model of Dent disease by targeted disruption of the Clcn5 gene. Clcn5 -/- mice had proteinuria due to strong reduction of apical proximal tubular endocytosis. Both receptor-mediated and fluid-phase endocytosis were affected, and the internalization of the apical transporters NaPi2 and Nhe3 (<a href="/entry/182307">182307</a>) was slowed. At steady state, however, both proteins were redistributed from the plasma membrane to intracellular vesicles. <a href="#22" class="mim-tip-reference" title="Piwon, N., Gunther, W., Schwake, M., Bosl, M. R., Jentsch, T. J. <strong>ClC-5 Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease.</strong> Nature 408: 369-373, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11099045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11099045</a>] [<a href="https://doi.org/10.1038/35042597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11099045">Piwon et al. (2000)</a> postulated that this may have been caused by an increased stimulation of luminal parathyroid hormone (PTH; <a href="/entry/168450">168450</a>) receptors (see <a href="/entry/168468">168468</a>) owing to the observed decreased tubular endocytosis of PTH. The rise in luminal PTH concentration should also have stimulated the hydroxylation of 25-hydroxyvitamin D3 to the active hormone. However, this would be counteracted by a urinary loss of the precursor 25-hydroxyvitamin D3. The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determined whether there would be hypercalciuria and kidney stones. <a href="#22" class="mim-tip-reference" title="Piwon, N., Gunther, W., Schwake, M., Bosl, M. R., Jentsch, T. J. <strong>ClC-5 Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease.</strong> Nature 408: 369-373, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11099045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11099045</a>] [<a href="https://doi.org/10.1038/35042597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11099045">Piwon et al. (2000)</a> showed that CLC5 is crucial for efficient endocytosis in the proximal tubule. CLC5 was the first intracellular chloride channel for which a role in vesicle trafficking was established. <a href="#22" class="mim-tip-reference" title="Piwon, N., Gunther, W., Schwake, M., Bosl, M. R., Jentsch, T. J. <strong>ClC-5 Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease.</strong> Nature 408: 369-373, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11099045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11099045</a>] [<a href="https://doi.org/10.1038/35042597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11099045">Piwon et al. (2000)</a> argued that their mouse model strongly suggested that alterations in hormones involved in calcium homeostasis, and hyperphosphaturia and hypocalciuria, are indirect effects of defective apical endocytosis of PTH and 25-hydroxyvitamin D3; this may explain how a defect in a chloride channel could lead to kidney stones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11099045" 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 Xenopus oocytes, <a href="#25" class="mim-tip-reference" title="Schwake, M., Friedrich, T., Jentsch, T. J. <strong>An internalization signal in ClC-5, an endosomal Cl- channel mutated in Dent's disease.</strong> J. Biol. Chem. 276: 12049-12054, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11116157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11116157</a>] [<a href="https://doi.org/10.1074/jbc.M010642200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11116157">Schwake et al. (2001)</a> found that mutations introduced into the C-terminal internalization PY motif of the Clcn5 gene increased surface expression and currents of the channel by about 2-fold. Further studies with the wildtype and mutant ubiquitin-protein ligase WWP2 (<a href="/entry/602308">602308</a>) and Rab5 (<a href="/entry/179512">179512</a>) indicated that the prolonged surface expression of PY-mutant Clcn5 resulted from changes in cellular trafficking of the channel, and that endocytosis of Clcn5 depended on the interaction of the internalization signal with these other endocytic proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11116157" 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="Christensen, E. I., Devuyst, O., Dom, G., Nielsen, R., Van Der Smissen, P., Verroust, P., Leruth, M., Guggino, W. B., Courtoy, P. J. <strong>Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules.</strong> Proc. Nat. Acad. Sci. 100: 8472-8477, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12815097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12815097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12815097[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.1432873100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12815097">Christensen et al. (2003)</a> tested whether the endocytic failure that results from loss of the CLCN5 channel in Dent disease and knockout mice primarily reflects a loss of reabsorption by the multiligand receptors megalin (<a href="/entry/600073">600073</a>) and cubilin (<a href="/entry/602997">602997</a>) caused by a trafficking defect. Impaired protein endocytosis in kidney proximal tubule cells of Clcn5 knockout mice was demonstrated by a major decreased uptake of (125)I-labeled beta-2-microglobulin (<a href="/entry/109700">109700</a>), but not of the fluid-phase tracer FITC-dextran; reduced labeling of endosomes by injected peroxidase and reduced labeling for the endogenous megalin/cubilin ligands vitamin D- and retinol-binding proteins; and urinary appearance of low molecular mass proteins and the selective cubilin ligand transferrin (<a href="/entry/190000">190000</a>). An overall decrease of megalin and cubilin in proximal tubule cells and their selective loss at the brush border was demonstrated. In contrast, total contents of the rate-limiting endocytic catalysts Rab5a and Rab7 (<a href="/entry/602298">602298</a>) were unaffected. Thus, impaired protein endocytosis caused by invalidation of Clcn5 primarily reflects a trafficking defect of megalin and cubilin in proximal tubule cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815097" 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="Novarino, G., Weinert, S., Rickheit, G., Jentsch, T. J. <strong>Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.</strong> Science 328: 1398-1401, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20430975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20430975</a>] [<a href="https://doi.org/10.1126/science.1188070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20430975">Novarino et al. (2010)</a> generated mice that carry the uncoupling E211A mutation that converts ClC5 into a pure chloride conductor. ATP-dependent acidification of renal endosomes was reduced in mice in which ClC5 was knocked out, but normal in mice carrying the E211A mutation. However, their proximal tubular endocytosis was also impaired. <a href="#19" class="mim-tip-reference" title="Novarino, G., Weinert, S., Rickheit, G., Jentsch, T. J. <strong>Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.</strong> Science 328: 1398-1401, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20430975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20430975</a>] [<a href="https://doi.org/10.1126/science.1188070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20430975">Novarino et al. (2010)</a> concluded that endosomal chloride concentration, which is raised by ClC5 in exchange for protons accumulated by the proton ATPase, may play a role in endocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20430975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Alex, P., Ye, M., Zachos, N. C., Sipes, J., Nguyen, T., Suhodrev, M., Gonzales, L., Arora, Z., Zhang, T., Centola, M., Guggino, S. E., Li, X. <strong>Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis.</strong> J. Immun. 184: 3988-3996, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20181886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20181886</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20181886[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/10.4049/jimmunol.0901657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20181886">Alex et al. (2010)</a> showed that loss of Clcn5 in mice exacerbated dextran sodium sulfate (DSS)-induced ulcerative colitis (<a href="/entry/266600">266600</a>), as measured by disease and histologic activity indices and myeloperoxidase (MPO; <a href="/entry/606989">606989</a>) activity. Multiplex serum cytokine analysis, as well as immunofluorescence and Western blot analyses of colonic mucosa, demonstrated a heightened Th1/Th17 profile with increased systemic and local expression of Tnfa (<a href="/entry/191160">191160</a>), Il6 (<a href="/entry/147620">147620</a>), and Il17 (<a href="/entry/603149">603149</a>) in Clcn5 -/- mice with DSS-induced ulcerative colitis. Baseline Il6 and phospho-Ikb (NFKBIA; <a href="/entry/164008">164008</a>) were high in Clcn5 -/- mice. Colitis in Clcn5 -/- mice could be attenuated by a high vitamin D diet. <a href="#2" class="mim-tip-reference" title="Alex, P., Ye, M., Zachos, N. C., Sipes, J., Nguyen, T., Suhodrev, M., Gonzales, L., Arora, Z., Zhang, T., Centola, M., Guggino, S. E., Li, X. <strong>Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis.</strong> J. Immun. 184: 3988-3996, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20181886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20181886</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20181886[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/10.4049/jimmunol.0901657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20181886">Alex et al. (2010)</a> concluded that CLCN5 is involved in the immunopathogenesis of ulcerative colitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20181886" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>14 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300008[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340620 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340620;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=rs151340620" 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=rs151340620" 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=RCV000012563 OR RCV000012564" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012563, RCV000012564" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012563...</a>
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<p>In affected members of a family with Dent disease (DENT1; <a href="/entry/300009">300009</a>), <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a G-to-A transition in the CLCN5 gene, resulting in a trp279-to-ter (W279X) substitution. The mutation was predicted to result in a loss of 469 amino acids from the D6 region to the C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V. <strong>Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).</strong> J. Clin. Invest. 99: 967-974, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9062355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9062355</a>] [<a href="https://doi.org/10.1172/JCI119262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9062355">Lloyd et al. (1997)</a> identified the W279X mutation in affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (<a href="/entry/308990">308990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9062355" 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> rs151340621 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340621;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/rs151340621?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=rs151340621" 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=rs151340621" 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=RCV000012565 OR RCV001723558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012565, RCV001723558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012565...</a>
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<p>In affected members of a family with Dent disease (DENT1; <a href="/entry/300009">300009</a>), <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a C-to-T transition in the CLCN5 gene, resulting in an arg648-to-ter (R648X) substitution. The mutation was predicted to result in a loss of 100 amino acids from the cytoplasmic C terminus of the protein, deleting domain D13, which is conserved in all eukaryotic chloride channel proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" 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="#14" class="mim-tip-reference" title="Lloyd, S. E., Gunther, W., Pearce, S. H. S., Thomson, A., Bianchi, M. L., Bosio, M., Craig, I. W., Fisher, S. E., Scheinman, S. J., Wrong, O., Jentsch, T. J., Thakker, R. V. <strong>Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders.</strong> Hum. Molec. Genet. 6: 1233-1239, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259268</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259268">Lloyd et al. (1997)</a> identified the R648X mutation in another family with Dent disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259268" 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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CLCN5, LEU200ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340622 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340622;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=rs151340622" 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=rs151340622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with Dent disease (DENT1; <a href="/entry/300009">300009</a>), <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a T-to-G transversion in the CLCN5 gene, resulting in a leu200-to-arg (L200R) substitution. The mutation was predicted to disrupt the charge distribution within domain D3 of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 DENT DISEASE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340623 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340623;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=rs151340623" 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=rs151340623" 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=RCV000012567" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012567" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012567</a>
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<p>In affected members of a family with Dent disease (DENT1; <a href="/entry/300009">300009</a>), <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a T-to-C transition in the CLCN5 gene, resulting in a ser520-to-pro (S520P) substitution. The mutation was predicted to disrupt a helix in D11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEPHROLITHIASIS, X-LINKED RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340624 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340624;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=rs151340624" 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=rs151340624" 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=RCV001004890 OR RCV003904829" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001004890, RCV003904829" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001004890...</a>
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<p>In affected members of a family with X-linked recessive nephrolithiasis (XRN; <a href="/entry/310468">310468</a>), <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a C-to-T transition in the CLCN5 gene, resulting in an arg704-to-ter (R704X) substitution. The mutation was predicted to result in a loss of 42 amino acids from the cytoplasmic C terminus of the protein, deleting domain D13, which is conserved in all eukaryotic chloride channel proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" 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>.0006 NEPHROLITHIASIS, X-LINKED RECESSIVE</strong>
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CLCN5, GLY506GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340625;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=rs151340625" 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=rs151340625" 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=RCV002266901 OR RCV002468922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002266901, RCV002468922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002266901...</a>
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<p>In affected members of a family with X-linked recessive nephrolithiasis, <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a G-to-A transition in the CLCN5 gene, resulting in a gly506-to-glu (G506E) substitution. The mutation was predicted to disrupt a charge within domain D11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 HYPOPHOSPHATEMIC RICKETS, X-LINKED RECESSIVE</strong>
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CLCN5, SER244LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340626;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=rs151340626" 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=rs151340626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012570 OR RCV000192274 OR RCV000485318 OR RCV002482856 OR RCV003398487" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012570, RCV000192274, RCV000485318, RCV002482856, RCV003398487" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012570...</a>
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<p>In affected members of an Italian family with X-linked recessive hypophosphatemic rickets (XLHRR; <a href="/entry/300554">300554</a>) reported by <a href="#4" class="mim-tip-reference" title="Bolino, A., Devoto, M., Enia, G., Zoccali, C., Weissenbach, J., Romeo, G. <strong>Genetic mapping in the Xp11.2 region of a new form of X-linked hypophosphatemic rickets.</strong> Europ. J. Hum. Genet. 1: 269-279, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7915957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7915957</a>] [<a href="https://doi.org/10.1159/000472424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7915957">Bolino et al. (1993)</a>, <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a> identified a C-to-T transition in the CLCN5 gene, resulting in a ser244-to-leu (S244L) substitution. The mutation was predicted to disrupt a helix in D5. Functional expression studies showed that the mutant S244L channel had reduced, but not abolished, chloride conductance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8559248+7915957" 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="#20" class="mim-tip-reference" title="Oudet, C., Martin-Coignard, D., Pannetier, S., Praud, E., Champion, G., Hanauer, A. <strong>A second family with XLRH displays the mutation S244L in the CLCN5 gene.</strong> Hum. Genet. 99: 781-784, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9187673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9187673</a>] [<a href="https://doi.org/10.1007/s004390050448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9187673">Oudet et al. (1997)</a> reported a second family with the S244L mutation but with a milder phenotype than that in the family reported by <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a>. The family reported by <a href="#20" class="mim-tip-reference" title="Oudet, C., Martin-Coignard, D., Pannetier, S., Praud, E., Champion, G., Hanauer, A. <strong>A second family with XLRH displays the mutation S244L in the CLCN5 gene.</strong> Hum. Genet. 99: 781-784, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9187673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9187673</a>] [<a href="https://doi.org/10.1007/s004390050448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9187673">Oudet et al. (1997)</a> had neither nephrocalcinosis nor nephrolithiasis. However, the affected individuals were significantly younger than those of the family reported by <a href="#15" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. <strong>A common molecular basis for three inherited kidney stone diseases.</strong> Nature 379: 445-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8559248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8559248</a>] [<a href="https://doi.org/10.1038/379445a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8559248">Lloyd et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8559248+9187673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS</strong>
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CLCN5, TRP343TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340627;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=rs151340627" 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=rs151340627" 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=RCV000012571" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012571" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012571</a>
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<p>In affected members of a Japanese family with low molecular weight proteinuria associated with hypercalciuria and nephrocalcinosis (<a href="/entry/308990">308990</a>), <a href="#16" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V. <strong>Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).</strong> J. Clin. Invest. 99: 967-974, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9062355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9062355</a>] [<a href="https://doi.org/10.1172/JCI119262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9062355">Lloyd et al. (1997)</a> identified a G-to-A transition in the CLCN5 gene, resulting in a trp343-to-ter (W343X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9062355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569540520 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569540520;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=rs1569540520" 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=rs1569540520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012572" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012572" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012572</a>
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<p>In affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (<a href="/entry/308990">308990</a>), <a href="#16" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V. <strong>Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).</strong> J. Clin. Invest. 99: 967-974, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9062355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9062355</a>] [<a href="https://doi.org/10.1172/JCI119262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9062355">Lloyd et al. (1997)</a> identified a 1-bp deletion (2085delC) in the CLCN5 gene, resulting in a frameshift and premature termination of the protein at codon 699. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9062355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0010 PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS</strong>
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CLCN5, ARG280PRO
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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> rs151340628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340628;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/rs151340628?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=rs151340628" 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=rs151340628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012573" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012573" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012573</a>
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<span class="mim-text-font">
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<p>In affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (<a href="/entry/308990">308990</a>), <a href="#16" class="mim-tip-reference" title="Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V. <strong>Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).</strong> J. Clin. Invest. 99: 967-974, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9062355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9062355</a>] [<a href="https://doi.org/10.1172/JCI119262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9062355">Lloyd et al. (1997)</a> identified an arg280-to-pro (R280P) mutation in the CLCN5 gene. Heterologous expression of this mutation in Xenopus oocytes demonstrated a 70% reduction in channel activity when compared with the wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9062355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 NEPHROLITHIASIS, X-LINKED RECESSIVE</strong>
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CLCN5, GLY57VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340629 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340629;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=rs151340629" 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=rs151340629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002468923" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468923" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468923</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 half-brothers, born of the same mother, with X-linked recessive nephrolithiasis (XRN; <a href="/entry/310468">310468</a>), <a href="#24" class="mim-tip-reference" title="Schurman, S. J., Norden, A. G. W., Scheinman, S. J. <strong>X-linked recessive nephrolithiasis: presentation and diagnosis in children.</strong> J. Pediat. 132: 859-862, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9602200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9602200</a>] [<a href="https://doi.org/10.1016/s0022-3476(98)70318-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9602200">Schurman et al. (1998)</a> identified a mutation in the CLCN5 gene, resulting in a gly57-to-val (G57V) substitution. The boys had been referred because of microhematuria and proteinuria noted on screening urinalysis. Family history showed renal failure after recurrent nephrolithiasis in a maternal grandfather and male cousin, and recurrent nephrolithiasis in an older brother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9602200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 DENT DISEASE 1</strong>
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CLCN5, ALU INS, EX11
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012575" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012575" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012575</a>
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<p><a href="#7" class="mim-tip-reference" title="Claverie-Martin, F., Gonzalez-Acosta, H., Flores, C., Anton-Gamero, M., Garcia-Nieto, V. <strong>De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease.</strong> Hum. Genet. 113: 480-485, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569459</a>] [<a href="https://doi.org/10.1007/s00439-003-0991-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569459">Claverie-Martin et al. (2003)</a> studied a Spanish patient with Dent disease (DENT1; <a href="/entry/300009">300009</a>) and found, by PCR amplification of the CLCN5 exons, an abnormally large exon 11. Sequence analysis showed an insertion in codon 650 of a 345-bp Alu element that had arisen de novo on the maternal chromosome. Polymorphism analysis indicated that the insertion occurred in the germline of the maternal grandfather. The presence of a long poly(A) tract and evidence for a 16-bp target-site duplication implied that the Alu element was integrated by retrotransposition. The mutation predicted a truncated CLC5 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Claverie-Martin, F., Flores, C., Anton-Gamero, M., Gonzalez-Acosta, H., Garcia-Nieto, V. <strong>The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping.</strong> J. Hum. Genet. 50: 370-374, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16041495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16041495</a>] [<a href="https://doi.org/10.1007/s10038-005-0265-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16041495">Claverie-Martin et al. (2005)</a> reported further studies of the Alu insertion in the family previously reported by <a href="#7" class="mim-tip-reference" title="Claverie-Martin, F., Gonzalez-Acosta, H., Flores, C., Anton-Gamero, M., Garcia-Nieto, V. <strong>De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease.</strong> Hum. Genet. 113: 480-485, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569459</a>] [<a href="https://doi.org/10.1007/s00439-003-0991-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569459">Claverie-Martin et al. (2003)</a>. PCR amplification of blood DNA showed that the Alu insertion resulted in aberrant splicing of the CLCN5 pre-mRNA and skipping of exon 11. The resultant truncated protein lacks part of the C terminus, including the PY and CBS2 domains, which are critical for sorting and chloride channel function. In addition, there were 2 conserved exonic splicing enhancer sequences in the site of insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16041495+14569459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 DENT DISEASE 1</strong>
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</h4>
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CLCN5, GLY260VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151340630 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151340630;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=rs151340630" 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=rs151340630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012576" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012576" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012576</a>
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<p><a href="#27" class="mim-tip-reference" title="Tosetto, E., Graziotto, R., Artifoni, L., Nachtigal, J., Cascone, C., Conz, P., Piva, M., Dell'Aquila, R., De Paoli Vitali, E., Citron, L., Nalesso, F., Antonello, A., Vertolli, U., Zagatti, R., Lupo, A., D'Angelo, A., Anglani, F., Gambaro, G. <strong>Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy.</strong> J. Hum. Genet. 51: 25-30, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247550</a>] [<a href="https://doi.org/10.1007/s10038-005-0317-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247550">Tosetto et al. (2006)</a> identified a 1070G-T transversion in exon 7 of the CLCN5 gene, resulting in a gly260-to-val (G260V) substitution, in 1 of 25 men from northern Italy with end-stage renal disease and renal stones. The findings were consistent with Dent disease (DENT1; <a href="/entry/300009">300009</a>). Examination of the family identified the G260V mutation in 2 additional young male relatives. Both had mild proteinuria, and one also had hypercalciuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16247550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 DENT DISEASE 1</strong>
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CLCN5, IVS8DS, G-T, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569540382 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569540382;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=rs1569540382" 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=rs1569540382" 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=RCV000012577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012577</a>
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<p>In a patient with Dent disease (DENT1; <a href="/entry/300009">300009</a>), <a href="#26" class="mim-tip-reference" title="Tosetto, E., Ceol, M,, Mezzabotta, F., Ammenti, A., Peruzzi, L., Caruso, M. R., Barbano, G., Vezzoli, G., Colussi, G., Vergine, G., Giordano, M., Glorioso, N., Degortes, S., Soldati, L., Sayer, J., D'Angelo, A., Anglani, F. <strong>Novel mutations of the CLCN5 gene including a complex allele and a 5-prime UTR mutation in Dent disease 1. (Letter)</strong> Clin. Genet. 76: 413-416, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19673950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19673950</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01212.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19673950">Tosetto et al. (2009)</a> identified a G-to-T transversion in intron 8 of the CLCN5, resulting in a splice site mutation and generation of an mRNA transcript lacking part of exon 8, which was confirmed by RT-PCR analysis. The mutation truncated the protein at codon 361. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19673950" 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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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Akuta1997" class="mim-anchor"></a>
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Akuta, N., Lloyd, S. E., Igarashi, T., Shiraga, H., Matsuyama, T., Yokoro, S., Cox, J. P. D., Thakker, R. V.
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<strong>Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis.</strong>
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Kidney Int. 52: 911-916, 1997.
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[<a href="https://doi.org/10.1038/ki.1997.412" target="_blank">Full Text</a>]
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Alex, P., Ye, M., Zachos, N. C., Sipes, J., Nguyen, T., Suhodrev, M., Gonzales, L., Arora, Z., Zhang, T., Centola, M., Guggino, S. E., Li, X.
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<strong>Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20181886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20181886</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20181886[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=20181886" 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/10.4049/jimmunol.0901657" target="_blank">Full Text</a>]
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<a id="Blair1995" class="mim-anchor"></a>
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Blair, H. J., Ho, M., Monaco, A. P., Fisher, S., Craig, I. W., Boyd, Y.
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<strong>High-resolution comparative mapping of the proximal region of the mouse X chromosome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8530041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1995.1146" target="_blank">Full Text</a>]
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Bolino, A., Devoto, M., Enia, G., Zoccali, C., Weissenbach, J., Romeo, G.
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<strong>Genetic mapping in the Xp11.2 region of a new form of X-linked hypophosphatemic rickets.</strong>
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Europ. J. Hum. Genet. 1: 269-279, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7915957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7915957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7915957" 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/10.1159/000472424" target="_blank">Full Text</a>]
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Christensen, E. I., Devuyst, O., Dom, G., Nielsen, R., Van Der Smissen, P., Verroust, P., Leruth, M., Guggino, W. B., Courtoy, P. J.
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<strong>Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules.</strong>
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Proc. Nat. Acad. Sci. 100: 8472-8477, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12815097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12815097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12815097[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=12815097" 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.1432873100" target="_blank">Full Text</a>]
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Claverie-Martin, F., Flores, C., Anton-Gamero, M., Gonzalez-Acosta, H., Garcia-Nieto, V.
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<strong>The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping.</strong>
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J. Hum. Genet. 50: 370-374, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16041495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16041495</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16041495" 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/s10038-005-0265-5" target="_blank">Full Text</a>]
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<a id="Claverie-Martin2003" class="mim-anchor"></a>
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Claverie-Martin, F., Gonzalez-Acosta, H., Flores, C., Anton-Gamero, M., Garcia-Nieto, V.
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<strong>De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease.</strong>
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Hum. Genet. 113: 480-485, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569459</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569459" 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/s00439-003-0991-8" target="_blank">Full Text</a>]
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<a id="Cox1999" class="mim-anchor"></a>
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Cox, J. P. D., Yamamoto, K., Christie, P. T., Wooding, C., Feest, T., Flinter, F. A., Goodyer, P. R., Leumann, E., Neuhaus, T., Reid, C., Williams, P. F., Wrong, O., Thakker, R. V.
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<strong>Renal chloride channel, CLCN5, mutations in Dent's disease.</strong>
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J. Bone Miner. Res. 14: 1536-1542, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10469281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10469281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10469281" 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/10.1359/jbmr.1999.14.9.1536" target="_blank">Full Text</a>]
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Devuyst, O., Christie, P. T., Courtoy, P. J., Beauwens, R., Thakker, R. V.
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<strong>Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease.</strong>
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Hum. Molec. Genet. 8: 247-257, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931332</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.2.247" target="_blank">Full Text</a>]
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<a id="Dutzler2002" class="mim-anchor"></a>
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Dutzler, R., Campbell, E. B., Cadene, M., Chait, B. T., MacKinnon, R.
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<strong>X-ray structure of a ClC chloride channel at 3.0 angstrom reveals the molecular basis of anion selectivity.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11796999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11796999</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11796999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/415287a" target="_blank">Full Text</a>]
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Fisher, S. E., Black, G. C. M., Lloyd, S. E., Hatchwell, E., Wrong, O., Thakker, R. V., Craig, I. W.
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<strong>Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis).</strong>
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Hum. Molec. Genet. 3: 2053-2059, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874126</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19131966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19131966</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19131966[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=19131966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/emboj.2008.284" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/3/2010
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 10/26/2010<br>Ada Hamosh - updated : 6/30/2010<br>Cassandra L. Kniffin - updated : 11/17/2008<br>Cassandra L. Kniffin - updated : 3/1/2006<br>Cassandra L. Kniffin - updated : 11/8/2005<br>Cassandra L. Kniffin - updated : 10/13/2005<br>Cassandra L. Kniffin - reorganized : 9/19/2005<br>Marla J. F. O'Neill - updated : 7/21/2005<br>Victor A. McKusick - updated : 11/24/2003<br>Victor A. McKusick - updated : 8/28/2003<br>Ada Hamosh - updated : 1/17/2002<br>Ada Hamosh - updated : 11/14/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Ada Hamosh - updated : 4/8/1999<br>Victor A. McKusick - updated : 9/4/1998<br>Michael J. Wright - updated : 8/25/1997<br>Victor A. McKusick - updated : 8/22/1997<br>Victor A. McKusick - updated : 5/9/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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 : 1/31/1996
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/22/2021<br>joanna : 02/20/2015<br>wwang : 12/7/2010<br>ckniffin : 12/3/2010<br>mgross : 10/27/2010<br>terry : 10/26/2010<br>alopez : 7/1/2010<br>terry : 6/30/2010<br>wwang : 11/24/2008<br>ckniffin : 11/17/2008<br>wwang : 3/7/2006<br>ckniffin : 3/1/2006<br>wwang : 11/17/2005<br>ckniffin : 11/8/2005<br>wwang : 10/24/2005<br>ckniffin : 10/13/2005<br>carol : 9/19/2005<br>carol : 9/19/2005<br>ckniffin : 9/7/2005<br>ckniffin : 9/1/2005<br>wwang : 7/22/2005<br>terry : 7/21/2005<br>terry : 4/21/2005<br>terry : 6/2/2004<br>alopez : 11/25/2003<br>terry : 11/24/2003<br>tkritzer : 8/28/2003<br>alopez : 1/22/2002<br>terry : 1/17/2002<br>mgross : 11/15/2000<br>terry : 11/14/2000<br>carol : 11/16/1999<br>terry : 11/9/1999<br>carol : 7/28/1999<br>kayiaros : 7/13/1999<br>carol : 5/24/1999<br>alopez : 4/8/1999<br>carol : 9/14/1998<br>terry : 9/4/1998<br>terry : 6/15/1998<br>dholmes : 6/10/1998<br>terry : 6/4/1998<br>terry : 11/20/1997<br>terry : 9/4/1997<br>terry : 8/25/1997<br>terry : 8/25/1997<br>terry : 8/25/1997<br>terry : 8/25/1997<br>terry : 8/22/1997<br>terry : 8/11/1997<br>terry : 8/11/1997<br>alopez : 6/27/1997<br>alopez : 5/9/1997<br>alopez : 5/9/1997<br>alopez : 5/7/1997<br>joanna : 2/1/1996<br>mark : 1/31/1996
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300008
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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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CHLORIDE CHANNEL 5; CLCN5
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CHLORIDE CHANNEL, VOLTAGE-GATED, K2; CLCK2<br />
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CLC5
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CLCN5</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 444645005, 717789008;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: Xp11.23
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Genomic coordinates <span class="small">(GRCh38)</span> : X:49,922,596-50,099,230 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="4">
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<span class="mim-font">
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Xp11.23
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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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Dent disease 1
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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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300009
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
X-linked recessive
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
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Hypophosphatemic rickets
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
300554
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Nephrolithiasis, type I
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
310468
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
308990
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
X-linked recessive
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<span class="mim-text-font">
|
|
<p>The CLCN5 gene encodes a voltage-gated chloride ion channel that belongs to a distinct branch of the chloride channel (CLC) family, which also includes CLCN3 (600580) and CLCN4 (302910) (Fisher et al., 1995). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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<span class="mim-text-font">
|
|
<p>By positional cloning of a microdeletion at chromosome Xp11.22 identified in a family with Dent disease (DENT1; 300009), Fisher et al. (1994) isolated a coding sequence from a human kidney cDNA library. Sequence analysis suggested that CLCN5, which they termed CLCK2, encoded a new member of the CLC family of voltage-gated chloride channels. A 9.5-kb mRNA transcript was expressed predominantly in the kidney. </p><p>Fisher et al. (1995) described the isolation and characterization of the complete open reading frame of CLCN5, which encodes a deduced 746-amino acid protein with significant homology to all known members of the family of voltage-gated chloride channels. </p>
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
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<p>Fisher et al. (1995) determined that the CLCN5 gene contains 12 exons and spans 25 to 30 kb of genomic DNA. </p>
|
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</span>
|
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<div>
|
|
<br />
|
|
</div>
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|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<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">
|
|
<p>By positional cloning, Fisher et al. (1994) identified the CLCN5 gene within the minimum candidate region for Dent disease (DENT1; 300009) on Xp11.22. </p><p>In the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, Blair et al. (1995) demonstrated the location of the Clcn5 gene in relation to others. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
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<span class="mim-text-font">
|
|
<p>Dutzler et al. (2002) presented the x-ray structures of 2 prokaryotic CLC chloride channels, from Salmonella typhimurium and E. coli, at 3.0 and 3.5 angstroms, respectively. Both structures revealed 2 identical pores, each pore being formed by a separate subunit contained within a homodimeric membrane protein. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Gunther et al. (1998) showed that the CLCN5 gene was expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression was highest below the brush border in a region densely packed with endocytotic vesicles, where CLC5 colocalizes with the H(+)-ATPase and with internalized proteins early after uptake. CLCN5 localized to apical intracellular vesicles in intercalated cells of the collecting duct, and colocalized with the proton pump in alpha-intercalated cells. In transfected cells, CLC5 colocalized with endocytosed alpha-2-macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant led to enlarged early endosomes that stained for CLC5. Gunther et al. (1998) suggested that CLC5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent disease. </p><p>Devuyst et al. (1999) raised specific antisera against human CLC5 and identified by immunoblotting an 83-kD band corresponding to CLC5 in human kidney cortex and medulla. Immunohistochemistry revealed CLC5 expression in the epithelial cells lining the proximal tubules and the thick ascending limbs of the Henle loop, and in the intercalated cells of the collecting ducts. Subcellular fractionation studies of human kidney established that CLC5 distribution was most closely associated with that of Rab4, a marker of recycling early endosomes. Confocal microscopy using the proximal tubular cell model of opossum kidney cells, which endogenously express CLC5, revealed that CLC5 colocalized with the albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway. The expression of CLC5 at multiple sites in the kidney explained the proteinuria and hypercalciuria which characterize Dent disease. </p><p>As described by Novarino et al. (2010), CLC5 is a 2-chloride (Cl-)/proton (H+) exchanger rather than a chloride channel (see Picollo and Pusch, 2005, Scheel et al., 2005, and Zifarelli and Pusch, 2009). </p>
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</span>
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lloyd et al. (1996) identified 11 mutations in the CLCN5 gene in affected members of 8 kindreds with Dent disease-1 (300009) (see, e.g., 300008.0001-300008.0004), 2 families with X-linked recessive nephrolithiasis (XRN; 310468; 300008.0005-300008.0006), and 1 family with X-linked recessive hypophosphatemic rickets (XLHRR; 300554; 300008.0007). All 4 missense mutations were confined to the predicted transmembrane domains. In vitro functional expression studies showed that the mutations markedly reduced or abolished outwardly rectifying chloride currents. </p><p>In affected members from 4 unrelated Japanese kindreds with low molecular weight proteinuria (308990), Lloyd et al. (1997) identified 4 different mutations in the CLCN5 gene (300008.0001; 300008.0008-300008.0010). Nakazato et al. (1997) identified mutations in the CLCN5 gene in affected members of 2 Japanese families with low molecular weight proteinuria. Akuta et al. (1997) identified mutations in the CLCN5 gene in 7 of 10 unrelated Japanese patients with low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. They estimated that over 70% of Japanese patients with the disorder have mutations in the CLCN5 gene. </p><p>In 8 unrelated patients with Dent disease, Cox et al. (1999) found 3 nonsense mutations, 4 deletions of single codons, and 1 acceptor splice consensus sequence mutation in the CLCN5 gene. None of these mutations was found in a study of unrelated normal individuals. All of the mutations predicted truncated chloride channels that were likely to result in a functional loss. </p><p>After heterologous expression of various mutant CLCN5 cDNAs in Xenopus oocytes, Ludwig et al. (2005) observed that except for the R516W and R648X (300008.0002) variants, none of the mutated proteins induced functional chloride currents or reached the plasma membrane. The tested missense mutations were distributed over different transmembrane regions, implying that correct channel structure and orientation in the membrane is not only a prerequisite for proper CLCN5 function but also for Golgi exit. The R648X mutant, although functionally compromised (30% of wildtype current), displayed a significant increase in surface expression. </p><p>Tosetto et al. (2009) identified mutations in the CLCN5 gene, including 15 novel mutations (see, e.g., 300008.0014), in 16 (53%) of 30 mostly Italian patients with a clinical suspicion of Dent disease. Most of the missense mutations were predicted to occur in the helix regions involved in the CLCN5 dimer interface. </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>Piwon et al. (2000) created a mouse model of Dent disease by targeted disruption of the Clcn5 gene. Clcn5 -/- mice had proteinuria due to strong reduction of apical proximal tubular endocytosis. Both receptor-mediated and fluid-phase endocytosis were affected, and the internalization of the apical transporters NaPi2 and Nhe3 (182307) was slowed. At steady state, however, both proteins were redistributed from the plasma membrane to intracellular vesicles. Piwon et al. (2000) postulated that this may have been caused by an increased stimulation of luminal parathyroid hormone (PTH; 168450) receptors (see 168468) owing to the observed decreased tubular endocytosis of PTH. The rise in luminal PTH concentration should also have stimulated the hydroxylation of 25-hydroxyvitamin D3 to the active hormone. However, this would be counteracted by a urinary loss of the precursor 25-hydroxyvitamin D3. The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determined whether there would be hypercalciuria and kidney stones. Piwon et al. (2000) showed that CLC5 is crucial for efficient endocytosis in the proximal tubule. CLC5 was the first intracellular chloride channel for which a role in vesicle trafficking was established. Piwon et al. (2000) argued that their mouse model strongly suggested that alterations in hormones involved in calcium homeostasis, and hyperphosphaturia and hypocalciuria, are indirect effects of defective apical endocytosis of PTH and 25-hydroxyvitamin D3; this may explain how a defect in a chloride channel could lead to kidney stones. </p><p>In Xenopus oocytes, Schwake et al. (2001) found that mutations introduced into the C-terminal internalization PY motif of the Clcn5 gene increased surface expression and currents of the channel by about 2-fold. Further studies with the wildtype and mutant ubiquitin-protein ligase WWP2 (602308) and Rab5 (179512) indicated that the prolonged surface expression of PY-mutant Clcn5 resulted from changes in cellular trafficking of the channel, and that endocytosis of Clcn5 depended on the interaction of the internalization signal with these other endocytic proteins. </p><p>Christensen et al. (2003) tested whether the endocytic failure that results from loss of the CLCN5 channel in Dent disease and knockout mice primarily reflects a loss of reabsorption by the multiligand receptors megalin (600073) and cubilin (602997) caused by a trafficking defect. Impaired protein endocytosis in kidney proximal tubule cells of Clcn5 knockout mice was demonstrated by a major decreased uptake of (125)I-labeled beta-2-microglobulin (109700), but not of the fluid-phase tracer FITC-dextran; reduced labeling of endosomes by injected peroxidase and reduced labeling for the endogenous megalin/cubilin ligands vitamin D- and retinol-binding proteins; and urinary appearance of low molecular mass proteins and the selective cubilin ligand transferrin (190000). An overall decrease of megalin and cubilin in proximal tubule cells and their selective loss at the brush border was demonstrated. In contrast, total contents of the rate-limiting endocytic catalysts Rab5a and Rab7 (602298) were unaffected. Thus, impaired protein endocytosis caused by invalidation of Clcn5 primarily reflects a trafficking defect of megalin and cubilin in proximal tubule cells. </p><p>Novarino et al. (2010) generated mice that carry the uncoupling E211A mutation that converts ClC5 into a pure chloride conductor. ATP-dependent acidification of renal endosomes was reduced in mice in which ClC5 was knocked out, but normal in mice carrying the E211A mutation. However, their proximal tubular endocytosis was also impaired. Novarino et al. (2010) concluded that endosomal chloride concentration, which is raised by ClC5 in exchange for protons accumulated by the proton ATPase, may play a role in endocytosis. </p><p>Alex et al. (2010) showed that loss of Clcn5 in mice exacerbated dextran sodium sulfate (DSS)-induced ulcerative colitis (266600), as measured by disease and histologic activity indices and myeloperoxidase (MPO; 606989) activity. Multiplex serum cytokine analysis, as well as immunofluorescence and Western blot analyses of colonic mucosa, demonstrated a heightened Th1/Th17 profile with increased systemic and local expression of Tnfa (191160), Il6 (147620), and Il17 (603149) in Clcn5 -/- mice with DSS-induced ulcerative colitis. Baseline Il6 and phospho-Ikb (NFKBIA; 164008) were high in Clcn5 -/- mice. Colitis in Clcn5 -/- mice could be attenuated by a high vitamin D diet. Alex et al. (2010) concluded that CLCN5 is involved in the immunopathogenesis of ulcerative colitis. </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>14 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 DENT DISEASE 1</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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PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS, INCLUDED
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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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CLCN5, TRP279TER
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<br />
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SNP: rs151340620,
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ClinVar: RCV000012563, RCV000012564
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a G-to-A transition in the CLCN5 gene, resulting in a trp279-to-ter (W279X) substitution. The mutation was predicted to result in a loss of 469 amino acids from the D6 region to the C terminus. </p><p>Lloyd et al. (1997) identified the W279X mutation in affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (308990). </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 DENT DISEASE 1</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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CLCN5, ARG648TER
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<br />
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SNP: rs151340621,
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gnomAD: rs151340621,
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ClinVar: RCV000012565, RCV001723558
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a C-to-T transition in the CLCN5 gene, resulting in an arg648-to-ter (R648X) substitution. The mutation was predicted to result in a loss of 100 amino acids from the cytoplasmic C terminus of the protein, deleting domain D13, which is conserved in all eukaryotic chloride channel proteins. </p><p>Lloyd et al. (1997) identified the R648X mutation in another family with Dent disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 DENT DISEASE 1</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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CLCN5, LEU200ARG
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<br />
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SNP: rs151340622,
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ClinVar: RCV000012566
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a T-to-G transversion in the CLCN5 gene, resulting in a leu200-to-arg (L200R) substitution. The mutation was predicted to disrupt the charge distribution within domain D3 of the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 DENT DISEASE 1</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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CLCN5, SER520PRO
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<br />
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SNP: rs151340623,
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ClinVar: RCV000012567
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a T-to-C transition in the CLCN5 gene, resulting in a ser520-to-pro (S520P) substitution. The mutation was predicted to disrupt a helix in D11. </p>
|
|
</span>
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</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEPHROLITHIASIS, X-LINKED RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLCN5, ARG704TER
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|
|
<br />
|
|
|
|
SNP: rs151340624,
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|
|
ClinVar: RCV001004890, RCV003904829
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with X-linked recessive nephrolithiasis (XRN; 310468), Lloyd et al. (1996) identified a C-to-T transition in the CLCN5 gene, resulting in an arg704-to-ter (R704X) substitution. The mutation was predicted to result in a loss of 42 amino acids from the cytoplasmic C terminus of the protein, deleting domain D13, which is conserved in all eukaryotic chloride channel proteins. </p>
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEPHROLITHIASIS, X-LINKED RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLCN5, GLY506GLU
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|
|
<br />
|
|
|
|
SNP: rs151340625,
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|
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|
|
ClinVar: RCV002266901, RCV002468922
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|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with X-linked recessive nephrolithiasis, Lloyd et al. (1996) identified a G-to-A transition in the CLCN5 gene, resulting in a gly506-to-glu (G506E) substitution. The mutation was predicted to disrupt a charge within domain D11. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPOPHOSPHATEMIC RICKETS, X-LINKED RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLCN5, SER244LEU
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|
|
<br />
|
|
|
|
SNP: rs151340626,
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|
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|
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|
|
|
ClinVar: RCV000012570, RCV000192274, RCV000485318, RCV002482856, RCV003398487
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family with X-linked recessive hypophosphatemic rickets (XLHRR; 300554) reported by Bolino et al. (1993), Lloyd et al. (1996) identified a C-to-T transition in the CLCN5 gene, resulting in a ser244-to-leu (S244L) substitution. The mutation was predicted to disrupt a helix in D5. Functional expression studies showed that the mutant S244L channel had reduced, but not abolished, chloride conductance. </p><p>Oudet et al. (1997) reported a second family with the S244L mutation but with a milder phenotype than that in the family reported by Lloyd et al. (1996). The family reported by Oudet et al. (1997) had neither nephrocalcinosis nor nephrolithiasis. However, the affected individuals were significantly younger than those of the family reported by Lloyd et al. (1996). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
CLCN5, TRP343TER
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<br />
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|
|
SNP: rs151340627,
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|
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ClinVar: RCV000012571
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|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Japanese family with low molecular weight proteinuria associated with hypercalciuria and nephrocalcinosis (308990), Lloyd et al. (1997) identified a G-to-A transition in the CLCN5 gene, resulting in a trp343-to-ter (W343X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLCN5, 1-BP DEL, 2085C
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<br />
|
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|
|
SNP: rs1569540520,
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|
|
|
ClinVar: RCV000012572
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|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (308990), Lloyd et al. (1997) identified a 1-bp deletion (2085delC) in the CLCN5 gene, resulting in a frameshift and premature termination of the protein at codon 699. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PROTEINURIA, LOW MOLECULAR WEIGHT, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLCN5, ARG280PRO
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|
<br />
|
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|
|
SNP: rs151340628,
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|
|
gnomAD: rs151340628,
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|
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|
|
|
ClinVar: RCV000012573
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|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (308990), Lloyd et al. (1997) identified an arg280-to-pro (R280P) mutation in the CLCN5 gene. Heterologous expression of this mutation in Xenopus oocytes demonstrated a 70% reduction in channel activity when compared with the wildtype. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEPHROLITHIASIS, X-LINKED RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
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<span class="mim-text-font">
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CLCN5, GLY57VAL
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<br />
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SNP: rs151340629,
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ClinVar: RCV002468923
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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 half-brothers, born of the same mother, with X-linked recessive nephrolithiasis (XRN; 310468), Schurman et al. (1998) identified a mutation in the CLCN5 gene, resulting in a gly57-to-val (G57V) substitution. The boys had been referred because of microhematuria and proteinuria noted on screening urinalysis. Family history showed renal failure after recurrent nephrolithiasis in a maternal grandfather and male cousin, and recurrent nephrolithiasis in an older brother. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 DENT DISEASE 1</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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CLCN5, ALU INS, EX11
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<br />
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ClinVar: RCV000012575
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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>Claverie-Martin et al. (2003) studied a Spanish patient with Dent disease (DENT1; 300009) and found, by PCR amplification of the CLCN5 exons, an abnormally large exon 11. Sequence analysis showed an insertion in codon 650 of a 345-bp Alu element that had arisen de novo on the maternal chromosome. Polymorphism analysis indicated that the insertion occurred in the germline of the maternal grandfather. The presence of a long poly(A) tract and evidence for a 16-bp target-site duplication implied that the Alu element was integrated by retrotransposition. The mutation predicted a truncated CLC5 protein. </p><p>Claverie-Martin et al. (2005) reported further studies of the Alu insertion in the family previously reported by Claverie-Martin et al. (2003). PCR amplification of blood DNA showed that the Alu insertion resulted in aberrant splicing of the CLCN5 pre-mRNA and skipping of exon 11. The resultant truncated protein lacks part of the C terminus, including the PY and CBS2 domains, which are critical for sorting and chloride channel function. In addition, there were 2 conserved exonic splicing enhancer sequences in the site of insertion. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 DENT DISEASE 1</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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CLCN5, GLY260VAL
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<br />
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SNP: rs151340630,
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ClinVar: RCV000012576
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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>Tosetto et al. (2006) identified a 1070G-T transversion in exon 7 of the CLCN5 gene, resulting in a gly260-to-val (G260V) substitution, in 1 of 25 men from northern Italy with end-stage renal disease and renal stones. The findings were consistent with Dent disease (DENT1; 300009). Examination of the family identified the G260V mutation in 2 additional young male relatives. Both had mild proteinuria, and one also had hypercalciuria. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0014 DENT DISEASE 1</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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CLCN5, IVS8DS, G-T, +1
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<br />
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SNP: rs1569540382,
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ClinVar: RCV000012577
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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 patient with Dent disease (DENT1; 300009), Tosetto et al. (2009) identified a G-to-T transversion in intron 8 of the CLCN5, resulting in a splice site mutation and generation of an mRNA transcript lacking part of exon 8, which was confirmed by RT-PCR analysis. The mutation truncated the protein at codon 361. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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Christensen, E. I., Devuyst, O., Dom, G., Nielsen, R., Van Der Smissen, P., Verroust, P., Leruth, M., Guggino, W. B., Courtoy, P. J.
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Claverie-Martin, F., Flores, C., Anton-Gamero, M., Gonzalez-Acosta, H., Garcia-Nieto, V.
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<strong>The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping.</strong>
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J. Hum. Genet. 50: 370-374, 2005.
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Claverie-Martin, F., Gonzalez-Acosta, H., Flores, C., Anton-Gamero, M., Garcia-Nieto, V.
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<strong>De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease.</strong>
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Hum. Genet. 113: 480-485, 2003.
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<p class="mim-text-font">
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Cox, J. P. D., Yamamoto, K., Christie, P. T., Wooding, C., Feest, T., Flinter, F. A., Goodyer, P. R., Leumann, E., Neuhaus, T., Reid, C., Williams, P. F., Wrong, O., Thakker, R. V.
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Devuyst, O., Christie, P. T., Courtoy, P. J., Beauwens, R., Thakker, R. V.
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Hum. Molec. Genet. 8: 247-257, 1999.
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Dutzler, R., Campbell, E. B., Cadene, M., Chait, B. T., MacKinnon, R.
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<strong>X-ray structure of a ClC chloride channel at 3.0 angstrom reveals the molecular basis of anion selectivity.</strong>
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Nature 415: 287-294, 2002.
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Fisher, S. E., Black, G. C. M., Lloyd, S. E., Hatchwell, E., Wrong, O., Thakker, R. V., Craig, I. W.
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Hum. Molec. Genet. 3: 2053-2059, 1994.
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Fisher, S. E., Van Bakel, I., Lloyd, S. E., Pearce, S. H. S., Thakker, R. V., Craig, I. W.
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<strong>Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis).</strong>
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Gunther, W., Luchow, A., Cluzeaud, F., Vandewalle, A., Jentsch, T. J.
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<strong>ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.</strong>
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Proc. Nat. Acad. Sci. 95: 8075-8080, 1998.
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Lloyd, S. E., Gunther, W., Pearce, S. H. S., Thomson, A., Bianchi, M. L., Bosio, M., Craig, I. W., Fisher, S. E., Scheinman, S. J., Wrong, O., Jentsch, T. J., Thakker, R. V.
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Hum. Molec. Genet. 6: 1233-1239, 1997.
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Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V.
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Nature 379: 445-449, 1996.
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<p class="mim-text-font">
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Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V.
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<strong>Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).</strong>
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J. Clin. Invest. 99: 967-974, 1997.
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<p class="mim-text-font">
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Ludwig, M., Doroszewicz, J., Seyberth, H. W., Bokenkamp, A., Balluch, B., Nuutinen, M., Utsch, B., Waldegger, S.
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<strong>Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization.</strong>
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<p class="mim-text-font">
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Nakazato, H., Hattori, S., Furuse, A., Kawano, T., Karashima, S., Tsuruta, M., Yoshimuta, J., Endo, F., Matsuda, I.
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<strong>Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria.</strong>
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Kidney Int. 52: 895-900, 1997.
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[PubMed: 9328927]
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[Full Text: https://doi.org/10.1038/ki.1997.410]
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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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|
Novarino, G., Weinert, S., Rickheit, G., Jentsch, T. J.
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<strong>Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.</strong>
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Science 328: 1398-1401, 2010.
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[PubMed: 20430975]
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[Full Text: https://doi.org/10.1126/science.1188070]
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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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Oudet, C., Martin-Coignard, D., Pannetier, S., Praud, E., Champion, G., Hanauer, A.
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<strong>A second family with XLRH displays the mutation S244L in the CLCN5 gene.</strong>
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Hum. Genet. 99: 781-784, 1997.
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[PubMed: 9187673]
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[Full Text: https://doi.org/10.1007/s004390050448]
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</p>
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<li>
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<p class="mim-text-font">
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|
Picollo, A., Pusch, M.
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<strong>Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5.</strong>
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Nature 436: 420-423, 2005.
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[PubMed: 16034421]
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[Full Text: https://doi.org/10.1038/nature03720]
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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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|
Piwon, N., Gunther, W., Schwake, M., Bosl, M. R., Jentsch, T. J.
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|
<strong>ClC-5 Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease.</strong>
|
|
Nature 408: 369-373, 2000.
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|
[PubMed: 11099045]
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[Full Text: https://doi.org/10.1038/35042597]
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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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|
Scheel, O., Zdebik, A. A., Lourdel, S., Jentsch, T. J.
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|
<strong>Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins.</strong>
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|
Nature 436: 424-427, 2005.
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[PubMed: 16034422]
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|
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Tosetto, E., Ceol, M,, Mezzabotta, F., Ammenti, A., Peruzzi, L., Caruso, M. R., Barbano, G., Vezzoli, G., Colussi, G., Vergine, G., Giordano, M., Glorioso, N., Degortes, S., Soldati, L., Sayer, J., D'Angelo, A., Anglani, F.
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Cassandra L. Kniffin - updated : 12/3/2010<br>Paul J. Converse - updated : 10/26/2010<br>Ada Hamosh - updated : 6/30/2010<br>Cassandra L. Kniffin - updated : 11/17/2008<br>Cassandra L. Kniffin - updated : 3/1/2006<br>Cassandra L. Kniffin - updated : 11/8/2005<br>Cassandra L. Kniffin - updated : 10/13/2005<br>Cassandra L. Kniffin - reorganized : 9/19/2005<br>Marla J. F. O'Neill - updated : 7/21/2005<br>Victor A. McKusick - updated : 11/24/2003<br>Victor A. McKusick - updated : 8/28/2003<br>Ada Hamosh - updated : 1/17/2002<br>Ada Hamosh - updated : 11/14/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Ada Hamosh - updated : 4/8/1999<br>Victor A. McKusick - updated : 9/4/1998<br>Michael J. Wright - updated : 8/25/1997<br>Victor A. McKusick - updated : 8/22/1997<br>Victor A. McKusick - updated : 5/9/1997
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Victor A. McKusick : 1/31/1996
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