3657 lines
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Entry
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- *602727 - CHLORIDE CHANNEL 7; CLCN7
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602727</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602727">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000103249;t=ENST00000382745" 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=1186" 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=602727" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</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=ENSG00000103249;t=ENST00000382745" 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_001114331,NM_001287,XM_011522354" 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_001287" 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=602727" 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=04103&isoform_id=04103_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/CLCN7" 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/1177440,1857982,2467175,6980070,12644301,13436311,13544046,14149607,14336753,15215300,83318378,119606059,119606060,119606061,158256244,158257704,167466160,193783828,193785868,193786462,193788507,194388324,221045344,767986868,2462547393" 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/P51798" 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=1186" 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=ENSG00000103249;t=ENST00000382745" 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=CLCN7" 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=CLCN7" 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+1186" 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/CLCN7" 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:1186" 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/1186" 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=chr16&hgg_gene=ENST00000382745.9&hgg_start=1444935&hgg_end=1475028&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2025" 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/clcn7" 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=602727[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=602727[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/CLCN7/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/ENSG00000103249" 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=CLCN7" 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=CLCN7" 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=CLCN7" 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://structure.bmc.lu.se/idbase/CLCN7base/" 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=CLCN7&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/PA26552" 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:2025" 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/FBgn0033755.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:1347048" 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/CLCN7#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:1347048" 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/1186/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001887/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1186" 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=WBGene00000533;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-061103-196" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=CLCN7&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> 725050005<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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602727
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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 7; CLCN7
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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CLC7
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CLCN7" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CLCN7</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
|
Cytogenetic location: <a href="/geneMap/16/64?start=-3&limit=10&highlight=64">16p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:1444935-1475028&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'})">16:1,444,935-1,475,028</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618541,166600,611490" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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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>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/64?start=-3&limit=10&highlight=64">
|
|
16p13.3
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
|
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<td>
|
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<span class="mim-font">
|
|
Hypopigmentation, organomegaly, and delayed myelination and development
|
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|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618541"> 618541 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Osteopetrosis, autosomal dominant 2
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/166600"> 166600 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<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>
|
|
</td>
|
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</tr>
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<p><a href="#3" class="mim-tip-reference" title="Brandt, S., Jentsch, T. J. <strong>ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family.</strong> FEBS Lett. 377: 15-20, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8543009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8543009</a>] [<a href="https://doi.org/10.1016/0014-5793(95)01298-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8543009">Brandt and Jentsch (1995)</a> identified regions of chloride channel proteins that are highly conserved within a given branch of the CLCN family but show significant divergence between branches. By RT-PCR using degenerate oligonucleotides based on the CLCN6 (<a href="/entry/602726">602726</a>) sequence within these branch-specific regions, <a href="#3" class="mim-tip-reference" title="Brandt, S., Jentsch, T. J. <strong>ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family.</strong> FEBS Lett. 377: 15-20, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8543009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8543009</a>] [<a href="https://doi.org/10.1016/0014-5793(95)01298-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8543009">Brandt and Jentsch (1995)</a> cloned a rat brain cDNA encoding Clcn7. Using the rat Clcn7 cDNA to screen a human cerebral cortex cDNA library, they isolated a partial human CLCN7 cDNA which lacked about 15 codons at the 5-prime end. The predicted amino acid sequence of human CLCN7 is 45% identical to that of CLCN6 but only about 21 to 30% identical to the sequences of other known CLCNs. Therefore, <a href="#3" class="mim-tip-reference" title="Brandt, S., Jentsch, T. J. <strong>ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family.</strong> FEBS Lett. 377: 15-20, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8543009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8543009</a>] [<a href="https://doi.org/10.1016/0014-5793(95)01298-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8543009">Brandt and Jentsch (1995)</a> stated that CLCN6 and CLCN7 together define a new branch of the CLCN family. The human and rat CLCN7 protein sequences are 96% identical. Northern blot analysis revealed that CLCN7 is expressed broadly as an approximately 4.2-kb transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8543009" 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 fluorescence in situ hybridization, <a href="#3" class="mim-tip-reference" title="Brandt, S., Jentsch, T. J. <strong>ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family.</strong> FEBS Lett. 377: 15-20, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8543009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8543009</a>] [<a href="https://doi.org/10.1016/0014-5793(95)01298-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8543009">Brandt and Jentsch (1995)</a> mapped the CLCN7 gene to 16p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8543009" 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="#9" class="mim-tip-reference" title="Lange, P. F., Wartosch, L., Jentsch, T. J., Fuhrmann, J. C. <strong>ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function.</strong> Nature 440: 220-223, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16525474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16525474</a>] [<a href="https://doi.org/10.1038/nature04535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16525474">Lange et al. (2006)</a> showed that CLCN7 and OSTM1 (<a href="/entry/607649">607649</a>) proteins colocalize in late endosomes and lysosomes of various tissues, as well as in the ruffled border of bone-resorbing osteoclasts. Coimmunoprecipitations showed that CLCN7 and OSTM1 form a molecular complex and suggested that OSTM1 is a beta subunit of CLCN7. CLCN7 is required for OSTM1 to reach lysosomes, where the highly glycosylated OSTM1 luminal domain is cleaved. Protein but not RNA levels of Clcn7 are greatly reduced in grey-lethal mice, which lack Ostm1, suggesting that the Clcn7-Ostm1 interaction is important for protein stability. As Clcn7 protein levels in Ostm1-deficient tissues and cells, including osteoclasts, are decreased below 10% of normal levels, Ostm1 mutations probably cause osteopetrosis by impairing the acidification of the osteoclast resorption lacuna, which depends on Clcn7. <a href="#9" class="mim-tip-reference" title="Lange, P. F., Wartosch, L., Jentsch, T. J., Fuhrmann, J. C. <strong>ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function.</strong> Nature 440: 220-223, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16525474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16525474</a>] [<a href="https://doi.org/10.1038/nature04535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16525474">Lange et al. (2006)</a> concluded that their finding that grey-lethal mice, just like Clcn7-deficient mice, show lysosomal storage and neurodegeneration in addition to osteopetrosis implies a more general importance for Clcn7-Ostm1 complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16525474" 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="Graves, A. R., Curran, P. K., Smith, C. L., Mindell, J. A. <strong>The CI-/H+ antiporter CIC-7 is the primary chloride permeation pathway in lysosomes.</strong> Nature 453: 788-792, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18449189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18449189</a>] [<a href="https://doi.org/10.1038/nature06907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18449189">Graves et al. (2008)</a> directly demonstrated an anion transport pathway in lysosomes that has the defining characteristics of a CLC Cl(-)/H(+) antiporter and showed that this transporter is the predominant route for Cl(-) through the lysosomal membrane. Knockdown of Clc7 expression by short interfering RNA could essentially ablate this lysosomal Cl(-)/H(+) antiporter activity and could strongly diminish the ability of lysosomes to acidify in vivo. <a href="#5" class="mim-tip-reference" title="Graves, A. R., Curran, P. K., Smith, C. L., Mindell, J. A. <strong>The CI-/H+ antiporter CIC-7 is the primary chloride permeation pathway in lysosomes.</strong> Nature 453: 788-792, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18449189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18449189</a>] [<a href="https://doi.org/10.1038/nature06907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18449189">Graves et al. (2008)</a> concluded that CLC7 is a Cl(-)/H(+) antiporter, that it constitutes the major Cl(-) permeability of lysosomes, and that it is important in lysosomal acidification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18449189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Osteopetrosis, Autosomal Recessive 4</em></strong></p><p>
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Based on the similarity between the phenotype of patients with infantile malignant osteopetrosis (see OPTB4; <a href="/entry/611490">611490</a>) and that of mice with targeted disruption of the Clcn7 gene (see ANIMAL MODEL), which develop severe osteopetrosis and retinal degeneration, <a href="#7" class="mim-tip-reference" title="Kornak, U., Kasper, D., Bosl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., Jentsch, T. J. <strong>Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.</strong> Cell 104: 205-215, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11207362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11207362</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00206-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11207362">Kornak et al. (2001)</a> searched for mutations in the human CLCN7 gene in 12 patients with infantile osteopetrosis. They identified compound heterozygosity for a nonsense (Q555X; <a href="#0001">602727.0001</a>) and a missense (R762Q; <a href="#0002">602727.0002</a>) mutation in the CLCN7 gene in 1 patient with the disease who had early visual impairment. No retinal histology was available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11207362" 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="Blair, H. C., Borysenko, C. W., Villa, A., Schlesinger, P. H., Kalla, S. E., Yaroslavsky, B. B., Garcia-Palacios, V., Oakley, J. I., Orchard, P. J. <strong>In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects.</strong> J. Bone Miner. Res. 19: 1329-1338, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15231021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15231021</a>] [<a href="https://doi.org/10.1359/JBMR.040403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15231021">Blair et al. (2004)</a> grew CD14 cells from normal and 4 osteopetrotic human subjects in the presence of bone and studied their osteoclastic differentiation in vitro. The osteopetrotic cells showed defects in acid transport, organic matrix removal, and cell fusion with deficient attachment compared with the normal cells. Genotype analysis showed that cells from 2 patients compound heterozygous for TCIRG1 (<a href="/entry/604592">604592</a>) mutations had acid transport defects, whereas cells from 1 patient compound heterozygous for CLCN7 mutations had organic matrix removal defects. The cells with an attachment defect were from a patient who lacked TCIRG1 and CLCN7 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15231021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Osteopetrosis, Autosomal Dominant 2</em></strong></p><p>
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In affected individuals from 12 unrelated families with autosomal dominant osteopetrosis-2 (OPTA2; <a href="/entry/166600">166600</a>), <a href="#4" class="mim-tip-reference" title="Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W. <strong>Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.</strong> Hum. Molec. Genet. 10: 2861-2867, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741829</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741829">Cleiren et al. (2001)</a> identified heterozygosity for 7 different mutations in the CLCN7 gene (see, e.g., <a href="#0004">602727.0004</a> and <a href="#0005">602727.0005</a>). Analysis of microsatellite markers indicated that the mutations arose independently in each family. Among these families was the Danish family that <a href="#12" class="mim-tip-reference" title="Van Hul, W., Van Hul, E., Wuyts, W., Bollerslev, J., Gram, J., Benichou, O., Willems, P. J. <strong>The Albers-Schonberg disease (autosomal dominant osteopetrosis) gene is located on chromosome 1p21 in a region containing the macrophage colony stimulating factor (CSF-1) gene. (Abstract)</strong> Medizinische Genetik 9: 8 only, 1997."None>Van Hul et al. (1997)</a> initially linked to chromosome 1p21. Additionally, <a href="#4" class="mim-tip-reference" title="Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W. <strong>Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.</strong> Hum. Molec. Genet. 10: 2861-2867, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741829</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741829">Cleiren et al. (2001)</a> identified 1 patient with the severe autosomal recessive infantile form of osteopetrosis (OPTB4) who was homozygous for a CLCN7 missense mutation (L766P; <a href="#0003">602727.0003</a>), for which her asymptomatic parents were heterozygous. The authors hypothesized that OPTA2 reflects a dominant-negative effect, since loss-of-function mutations in CLCN7 do not cause abnormalities in heterozygous individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hypopigmentation, Organomegaly, and Delayed Myelination and Development</em></strong></p><p>
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In 2 unrelated children with hypopigmentation, organomegaly, and delayed myelination and development (HOD; <a href="/entry/618541">618541</a>), <a href="#10" class="mim-tip-reference" title="Nicoli, E.-R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., II, Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., and 15 others. <strong>Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification.</strong> Am. J. Hum. Genet. 104: 1127-1138, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31155284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31155284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31155284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31155284">Nicoli et al. (2019)</a> identified heterozygosity for the same de novo missense mutation in the CLCN7 gene (Y715C; <a href="#0007">602727.0007</a>). Neither child exhibited osteopetrosis. Functional analysis demonstrated that the mutation caused a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31155284" 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="#7" class="mim-tip-reference" title="Kornak, U., Kasper, D., Bosl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., Jentsch, T. J. <strong>Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.</strong> Cell 104: 205-215, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11207362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11207362</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00206-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11207362">Kornak et al. (2001)</a> observed that mice with targeted disruption of the Clcn7 gene (Clcn7 -/-) had severe osteopetrosis and retinal degeneration. Although osteoclasts were present in normal numbers, they failed to resorb bone because they could not acidify the extracellular resorption lacuna. Clcn7 was found to reside in late endosomal and lysosomal compartments. In osteoclasts it was highly expressed in the ruffled membrane, formed by the fusion of H(+) ATPase-containing vesicles, that secretes protons into the lacuna. The authors concluded that CLCN7 provides the chloride conductance required for an efficient proton pumping by the H(+) ATPase of the osteoclast ruffled membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11207362" 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="Kasper, D., Planells-Cases, R., Fuhrmann, J. C., Scheel, O., Zeitz, O., Ruether, K., Schmitt, A., Poet, M., Steinfeld, R., Schweizer, M., Kornak, U., Jentsch, T. J. <strong>Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration.</strong> EMBO J. 24: 1079-1091, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15706348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15706348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15706348[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/sj.emboj.7600576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15706348">Kasper et al. (2005)</a> showed that Clcn7 knockout mice, in addition to osteopetrosis, display neurodegeneration and severe lysosomal storage disease despite unchanged lysosomal pH in cultured neurons. Rescuing their bone phenotype by transgenic expression of Clcn7 in osteoclasts moderately increased the life span and revealed a further progression of the central nervous system pathology. Histologic analysis demonstrated an accumulation of electron-dense material in neurons, autofluorescent structures, microglial activation, and astrogliosis. As in human neuronal ceroid lipofuscinosis (see <a href="/entry/256730">256730</a>), there was a strong accumulation of subunit c of the mitochondrial ATP synthase (see <a href="/entry/603192">603192</a>) and increased amounts of lysosomal enzymes. Such alterations were minor or absent in Clcn3 (<a href="/entry/600580">600580</a>) knockout mice, despite a massive neurodegeneration. Osteopetrotic oc/oc mice, lacking a functional proton-ATPase a3 subunit (<a href="/entry/604592">604592</a>), showed no comparable retinal or neuronal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15706348" 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="#13" class="mim-tip-reference" title="Weinert, S., Jabs, S., Supanchart, C., Schweizer, M., Gimber, N., Richter, M., Rademann, J., Stauber, T., Kornak, U., Jentsch, T. J. <strong>Lysosomal pathology and osteopetrosis upon loss of H(+)-driven lysosomal Cl- accumulation.</strong> Science 328: 1401-1403, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20430974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20430974</a>] [<a href="https://doi.org/10.1126/science.1188072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20430974">Weinert et al. (2010)</a> generated mice carrying a point mutation converting Clc7 into an uncoupled chloride conductor. Despite maintaining lysosomal conductions and normal lysosomal pH, these Clcn7(unc/unc) mice showed lysosomal storage disease like mice lacking Clc7. However, their osteopetrosis was milder, and they lacked a coat color phenotype. <a href="#13" class="mim-tip-reference" title="Weinert, S., Jabs, S., Supanchart, C., Schweizer, M., Gimber, N., Richter, M., Rademann, J., Stauber, T., Kornak, U., Jentsch, T. J. <strong>Lysosomal pathology and osteopetrosis upon loss of H(+)-driven lysosomal Cl- accumulation.</strong> Science 328: 1401-1403, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20430974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20430974</a>] [<a href="https://doi.org/10.1126/science.1188072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20430974">Weinert et al. (2010)</a> concluded that only some roles of ClC7 Cl-/H+ exchange can be taken over by a chloride conductance. This conductance was even deleterious in Clcn7/unc heterozygote mice. Clcn7-null and Clcn7(unc/unc) mice accumulated less chloride in lysosomes than did wildtype mice. <a href="#13" class="mim-tip-reference" title="Weinert, S., Jabs, S., Supanchart, C., Schweizer, M., Gimber, N., Richter, M., Rademann, J., Stauber, T., Kornak, U., Jentsch, T. J. <strong>Lysosomal pathology and osteopetrosis upon loss of H(+)-driven lysosomal Cl- accumulation.</strong> Science 328: 1401-1403, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20430974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20430974</a>] [<a href="https://doi.org/10.1126/science.1188072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20430974">Weinert et al. (2010)</a> concluded that lowered lysosomal chloride may underlie their common phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20430974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Nicoli, E.-R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., II, Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., and 15 others. <strong>Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification.</strong> Am. J. Hum. Genet. 104: 1127-1138, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31155284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31155284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31155284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31155284">Nicoli et al. (2019)</a> generated mice with a knock-in of Clcn7 Y713C, the variant orthologous to the human CLCN7 Y715C variant (<a href="#0007">602727.0007</a>), and observed recapitulation of the human phenotype, including striking hair hypopigmentation; dermal fibroblasts with enlarged cytoplasmic vacuoles; lysosomal storage with intracellular vacuoles in the liver, spleen, and kidneys; brain myelination abnormalities; and enlarged cytoplasmic vacuoles in dermal fibroblasts that partially stained for Lamp1 (<a href="/entry/153330">153330</a>). Tibial sections from mutant mice revealed no osteopetrosis and showed an intact marrow cavity and normally organized trabecular and cortical structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31155284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Pressey, S. N., O'Donnell, K. J., Stauber, T., Fuhrmann, J. C., Tyynela, J., Jentsch, T. J., Cooper, J. D. <strong>Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC-6 or ClC-7/Ostm1.</strong> J. Neuropath. Exp. Neurol. 69: 1228-1246, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107136</a>] [<a href="https://doi.org/10.1097/NEN.0b013e3181ffe742" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107136">Pressey et al. (2010)</a> studied the neurologic phenotype of a Clcn7 knockout mouse model. The mutant mice had atrophy image of the cortex, corpus callosum, internal capsule, and cerebral peduncles at 4 weeks of age. The mouse brains also had early-onset and progressive astrocytosis of the thalamus and cortex. Microglial activation was identified in the same regions as the astrocytosis. There was also storage of carbohydrate material in neuronal lysosomes throughout the cortex and thalamus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21107136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the arg762-to-gln (R762Q) mutation that was identified in a patient with autosomal recessive osteopetrosis-4 (OPTB4; <a href="/entry/611490">611490</a>) by <a href="#7" class="mim-tip-reference" title="Kornak, U., Kasper, D., Bosl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., Jentsch, T. J. <strong>Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.</strong> Cell 104: 205-215, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11207362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11207362</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00206-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11207362">Kornak et al. (2001)</a>, see <a href="#0001">602727.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11207362" 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">rs121434434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434434;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=rs121434434" 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=rs121434434" 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=RCV000007265" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007265" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007265</a>
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<p>In a girl with autosomal recessive infantile malignant osteopetrosis (OPTB4; <a href="/entry/611490">611490</a>), born to second-cousin parents of Chinese ancestry, <a href="#4" class="mim-tip-reference" title="Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W. <strong>Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.</strong> Hum. Molec. Genet. 10: 2861-2867, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741829</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741829">Cleiren et al. (2001)</a> identified homozygosity for a T-to-C transition at codon 766 of the CLCN7 gene, leading to a leu766-to-pro (L766P) substitution. The substitution was located in the D13 stretch of the conserved CBS2 domain. The asymptomatic parents were heterozygous for the mutation, which was not found in 100 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741829" 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 OSTEOPETROSIS, AUTOSOMAL DOMINANT 2</strong>
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CLCN7, ARG767TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434435 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434435;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=rs121434435" 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=rs121434435" 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=RCV000007266 OR RCV000055846 OR RCV001851716" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007266, RCV000055846, RCV001851716" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007266...</a>
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<p>In a French family and an American family with autosomal dominant osteopetrosis (OPTA2; <a href="/entry/166600">166600</a>), previously studied by <a href="#1" class="mim-tip-reference" title="Benichou, O., Cleiren, E., Gram, J., Bollerslev, J., de Vernejoul, M.-C., Van Hul, W. <strong>Mapping of autosomal dominant osteopetrosis type II (Albers-Schonberg disease) to chromosome 16p13.3.</strong> Am. J. Hum. Genet. 69: 647-654, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468688</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11468688[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/323132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468688">Benichou et al. (2001)</a> and <a href="#14" class="mim-tip-reference" title="Yoneyama, T., Fowler, H. L., Pendleton, J. W., Sforza, P. P., Gerard, R. D., Lui, C. Y., Eldridge, T. H., Iranmanesh, A. <strong>Elevated serum levels of creatine kinase BB in autosomal dominant osteopetrosis type II--a family study.</strong> Clin. Genet. 42: 39-42, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1516225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1516225</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1992.tb03134.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1516225">Yoneyama et al. (1992)</a>, respectively, <a href="#4" class="mim-tip-reference" title="Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W. <strong>Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.</strong> Hum. Molec. Genet. 10: 2861-2867, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741829</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741829">Cleiren et al. (2001)</a> identified heterozygosity for a C-to-T transition at codon 767 of the CLCN7 gene, leading to an arg767-to-trp (R767W) substitution. The substitution abolished a positive charge within the conserved CBS2 domain of CLCN7. Analysis of microsatellite markers indicated that the mutation arose independently in each family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11741829+1516225+11468688" 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="0005" class="mim-anchor"></a>
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<h4>
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<strong>.0005 OSTEOPETROSIS, AUTOSOMAL DOMINANT 2</strong>
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CLCN7, 2-BP DEL, 2423AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2142364275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2142364275;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=rs2142364275" 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=rs2142364275" 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=RCV001899493 OR RCV002279772 OR RCV003147692" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001899493, RCV002279772, RCV003147692" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001899493...</a>
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<p>In a French family and an American family with autosomal dominant osteopetrosis (OPTA2; <a href="/entry/166600">166600</a>), <a href="#4" class="mim-tip-reference" title="Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W. <strong>Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.</strong> Hum. Molec. Genet. 10: 2861-2867, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741829</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741829">Cleiren et al. (2001)</a> identified heterozygosity for a dinucleotide deletion (2423delAG) in the C-terminal portion of CLCN7. The mutation was predicted to generate a frameshift and result in substitutions for the last 10 amino acids of the protein. The French family had previously been reported by <a href="#1" class="mim-tip-reference" title="Benichou, O., Cleiren, E., Gram, J., Bollerslev, J., de Vernejoul, M.-C., Van Hul, W. <strong>Mapping of autosomal dominant osteopetrosis type II (Albers-Schonberg disease) to chromosome 16p13.3.</strong> Am. J. Hum. Genet. 69: 647-654, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468688</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11468688[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/323132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468688">Benichou et al. (2001)</a>. Analysis of microsatellite markers indicated that the mutation arose independently in each family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11741829+11468688" 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 OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4</strong>
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CLCN7, ILE261PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434436 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434436;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=rs121434436" 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=rs121434436" 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=RCV000007268" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007268" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007268</a>
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<p>In a Chinese sister and brother with malignant osteopetrosis (OPTB4; <a href="/entry/611490">611490</a>), born of first-cousin parents, <a href="#8" class="mim-tip-reference" title="Lam, C.-W., Tong, S.-F., Wong, K., Luo, Y. F., Tang, H.-Y., Ha, S.-Y., Chan, M. H.-M. <strong>DNA-based diagnosis of malignant osteopetrosis by whole-genome scan using a single-nucleotide polymorphism microarray: standardization of molecular investigations of genetic diseases due to consanguinity.</strong> J. Hum. Genet. 52: 98-101, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033731</a>] [<a href="https://doi.org/10.1007/s10038-006-0075-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033731">Lam et al. (2007)</a> identified homozygosity for a c.781A-T transversion in exon 9 of the CLCN7 gene, resulting in an ile261-to-phe (I261F) substitution. Their unaffected parents and an unaffected brother were heterozygous for the mutation, which was not found in 50 Chinese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17033731" 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="0007" class="mim-anchor"></a>
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<h4>
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<strong>.0007 HYPOPIGMENTATION, ORGANOMEGALY, AND DELAYED MYELINATION AND DEVELOPMENT</strong>
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CLCN7, TYR715CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057517718 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057517718;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=rs1057517718" 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=rs1057517718" 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=RCV000412760 OR RCV000824813" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412760, RCV000824813" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412760...</a>
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<p>In a 22-month-old Caucasian girl and a 14-month-old Ghanaian boy with hypopigmentation, organomegaly, and delayed myelination and development (HOD; <a href="/entry/618541">618541</a>), <a href="#10" class="mim-tip-reference" title="Nicoli, E.-R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., II, Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., and 15 others. <strong>Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification.</strong> Am. J. Hum. Genet. 104: 1127-1138, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31155284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31155284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31155284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31155284">Nicoli et al. (2019)</a> identified heterozygosity for a de novo c.2144A-G transition (c.2144A-G, NM_001287.5) in exon 23 of the CLCN7 gene, resulting in a tyr715-to-cys (Y715C) substitution at a highly conserved residue within the C-terminal cytoplasmic domain. The mutation was not found in the unaffected parents or in the ExAC, gnomAD, ESP, or EVS databases. Functional analysis of chloride transport in transfected Xenopus oocytes demonstrated an approximately 3-fold increase in outward currents with the Y715C mutant compared to wildtype. Quantitative pH measurements in lysosomes from patient fibroblasts revealed a reduced pH compared to control; increased staining with acidotropic dye confirmed the lowered lysosomal pH. Large, variably sized cytoplasmic single- and double-membraned vacuoles, sometimes containing amorphous material and cellular debris, were present in fibroblasts from both probands, and overexpressing the Y715C variant in control fibroblasts dramatically recapitulated the mutant phenotype of enlarged cytoplasmic vacuoles. Chloroquine treatment of patient dermal fibroblasts increased lysosomal pH in a dose-dependent manner and reduced the abundance of large vacuoles in the mutant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31155284" 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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Nicoli, E.-R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., II, Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., and 15 others.
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<strong>Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31155284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31155284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31155284[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=31155284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hilary J. Vernon - updated : 08/30/2024
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Marla J. F. O'Neill - updated : 08/15/2019<br>Bao Lige - updated : 09/18/2018<br>Marla J. F. O'Neill - updated : 09/04/2018<br>Ada Hamosh - updated : 6/30/2010<br>Ada Hamosh - updated : 7/9/2008<br>Marla J. F. O'Neill - updated : 10/3/2007<br>Victor A. McKusick - updated : 9/4/2007<br>Ada Hamosh - updated : 12/6/2006<br>George E. Tiller - updated : 10/14/2002<br>Stylianos E. Antonarakis - updated : 1/29/2001
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 6/17/1998
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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 : 08/30/2024
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carol : 02/22/2022<br>alopez : 08/15/2019<br>carol : 09/19/2018<br>mgross : 09/18/2018<br>carol : 09/04/2018<br>carol : 05/26/2015<br>alopez : 7/1/2010<br>terry : 6/30/2010<br>wwang : 7/15/2008<br>terry : 7/9/2008<br>carol : 2/19/2008<br>carol : 10/3/2007<br>alopez : 9/6/2007<br>terry : 9/4/2007<br>wwang : 6/6/2007<br>alopez : 12/15/2006<br>terry : 12/6/2006<br>tkritzer : 3/10/2003<br>tkritzer : 3/7/2003<br>cwells : 10/16/2002<br>cwells : 10/16/2002<br>cwells : 10/14/2002<br>mgross : 1/29/2001<br>psherman : 6/18/1998<br>psherman : 6/18/1998
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<span class="mim-font">
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<strong>*</strong> 602727
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CHLORIDE CHANNEL 7; CLCN7
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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CLC7
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CLCN7</em></strong>
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<strong>SNOMEDCT:</strong> 725050005;
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Cytogenetic location: 16p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:1,444,935-1,475,028 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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16p13.3
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<span class="mim-font">
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Hypopigmentation, organomegaly, and delayed myelination and development
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<span class="mim-font">
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618541
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Autosomal dominant
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3
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Osteopetrosis, autosomal dominant 2
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166600
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Osteopetrosis, autosomal recessive 4
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<span class="mim-font">
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611490
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>Brandt and Jentsch (1995) identified regions of chloride channel proteins that are highly conserved within a given branch of the CLCN family but show significant divergence between branches. By RT-PCR using degenerate oligonucleotides based on the CLCN6 (602726) sequence within these branch-specific regions, Brandt and Jentsch (1995) cloned a rat brain cDNA encoding Clcn7. Using the rat Clcn7 cDNA to screen a human cerebral cortex cDNA library, they isolated a partial human CLCN7 cDNA which lacked about 15 codons at the 5-prime end. The predicted amino acid sequence of human CLCN7 is 45% identical to that of CLCN6 but only about 21 to 30% identical to the sequences of other known CLCNs. Therefore, Brandt and Jentsch (1995) stated that CLCN6 and CLCN7 together define a new branch of the CLCN family. The human and rat CLCN7 protein sequences are 96% identical. Northern blot analysis revealed that CLCN7 is expressed broadly as an approximately 4.2-kb transcript. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization, Brandt and Jentsch (1995) mapped the CLCN7 gene to 16p13. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lange et al. (2006) showed that CLCN7 and OSTM1 (607649) proteins colocalize in late endosomes and lysosomes of various tissues, as well as in the ruffled border of bone-resorbing osteoclasts. Coimmunoprecipitations showed that CLCN7 and OSTM1 form a molecular complex and suggested that OSTM1 is a beta subunit of CLCN7. CLCN7 is required for OSTM1 to reach lysosomes, where the highly glycosylated OSTM1 luminal domain is cleaved. Protein but not RNA levels of Clcn7 are greatly reduced in grey-lethal mice, which lack Ostm1, suggesting that the Clcn7-Ostm1 interaction is important for protein stability. As Clcn7 protein levels in Ostm1-deficient tissues and cells, including osteoclasts, are decreased below 10% of normal levels, Ostm1 mutations probably cause osteopetrosis by impairing the acidification of the osteoclast resorption lacuna, which depends on Clcn7. Lange et al. (2006) concluded that their finding that grey-lethal mice, just like Clcn7-deficient mice, show lysosomal storage and neurodegeneration in addition to osteopetrosis implies a more general importance for Clcn7-Ostm1 complexes. </p><p>Graves et al. (2008) directly demonstrated an anion transport pathway in lysosomes that has the defining characteristics of a CLC Cl(-)/H(+) antiporter and showed that this transporter is the predominant route for Cl(-) through the lysosomal membrane. Knockdown of Clc7 expression by short interfering RNA could essentially ablate this lysosomal Cl(-)/H(+) antiporter activity and could strongly diminish the ability of lysosomes to acidify in vivo. Graves et al. (2008) concluded that CLC7 is a Cl(-)/H(+) antiporter, that it constitutes the major Cl(-) permeability of lysosomes, and that it is important in lysosomal acidification. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Osteopetrosis, Autosomal Recessive 4</em></strong></p><p>
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Based on the similarity between the phenotype of patients with infantile malignant osteopetrosis (see OPTB4; 611490) and that of mice with targeted disruption of the Clcn7 gene (see ANIMAL MODEL), which develop severe osteopetrosis and retinal degeneration, Kornak et al. (2001) searched for mutations in the human CLCN7 gene in 12 patients with infantile osteopetrosis. They identified compound heterozygosity for a nonsense (Q555X; 602727.0001) and a missense (R762Q; 602727.0002) mutation in the CLCN7 gene in 1 patient with the disease who had early visual impairment. No retinal histology was available. </p><p>Blair et al. (2004) grew CD14 cells from normal and 4 osteopetrotic human subjects in the presence of bone and studied their osteoclastic differentiation in vitro. The osteopetrotic cells showed defects in acid transport, organic matrix removal, and cell fusion with deficient attachment compared with the normal cells. Genotype analysis showed that cells from 2 patients compound heterozygous for TCIRG1 (604592) mutations had acid transport defects, whereas cells from 1 patient compound heterozygous for CLCN7 mutations had organic matrix removal defects. The cells with an attachment defect were from a patient who lacked TCIRG1 and CLCN7 mutations. </p><p><strong><em>Osteopetrosis, Autosomal Dominant 2</em></strong></p><p>
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In affected individuals from 12 unrelated families with autosomal dominant osteopetrosis-2 (OPTA2; 166600), Cleiren et al. (2001) identified heterozygosity for 7 different mutations in the CLCN7 gene (see, e.g., 602727.0004 and 602727.0005). Analysis of microsatellite markers indicated that the mutations arose independently in each family. Among these families was the Danish family that Van Hul et al. (1997) initially linked to chromosome 1p21. Additionally, Cleiren et al. (2001) identified 1 patient with the severe autosomal recessive infantile form of osteopetrosis (OPTB4) who was homozygous for a CLCN7 missense mutation (L766P; 602727.0003), for which her asymptomatic parents were heterozygous. The authors hypothesized that OPTA2 reflects a dominant-negative effect, since loss-of-function mutations in CLCN7 do not cause abnormalities in heterozygous individuals. </p><p><strong><em>Hypopigmentation, Organomegaly, and Delayed Myelination and Development</em></strong></p><p>
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In 2 unrelated children with hypopigmentation, organomegaly, and delayed myelination and development (HOD; 618541), Nicoli et al. (2019) identified heterozygosity for the same de novo missense mutation in the CLCN7 gene (Y715C; 602727.0007). Neither child exhibited osteopetrosis. Functional analysis demonstrated that the mutation caused a gain of function. </p>
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</span>
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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>Kornak et al. (2001) observed that mice with targeted disruption of the Clcn7 gene (Clcn7 -/-) had severe osteopetrosis and retinal degeneration. Although osteoclasts were present in normal numbers, they failed to resorb bone because they could not acidify the extracellular resorption lacuna. Clcn7 was found to reside in late endosomal and lysosomal compartments. In osteoclasts it was highly expressed in the ruffled membrane, formed by the fusion of H(+) ATPase-containing vesicles, that secretes protons into the lacuna. The authors concluded that CLCN7 provides the chloride conductance required for an efficient proton pumping by the H(+) ATPase of the osteoclast ruffled membrane. </p><p>Kasper et al. (2005) showed that Clcn7 knockout mice, in addition to osteopetrosis, display neurodegeneration and severe lysosomal storage disease despite unchanged lysosomal pH in cultured neurons. Rescuing their bone phenotype by transgenic expression of Clcn7 in osteoclasts moderately increased the life span and revealed a further progression of the central nervous system pathology. Histologic analysis demonstrated an accumulation of electron-dense material in neurons, autofluorescent structures, microglial activation, and astrogliosis. As in human neuronal ceroid lipofuscinosis (see 256730), there was a strong accumulation of subunit c of the mitochondrial ATP synthase (see 603192) and increased amounts of lysosomal enzymes. Such alterations were minor or absent in Clcn3 (600580) knockout mice, despite a massive neurodegeneration. Osteopetrotic oc/oc mice, lacking a functional proton-ATPase a3 subunit (604592), showed no comparable retinal or neuronal degeneration. </p><p>Weinert et al. (2010) generated mice carrying a point mutation converting Clc7 into an uncoupled chloride conductor. Despite maintaining lysosomal conductions and normal lysosomal pH, these Clcn7(unc/unc) mice showed lysosomal storage disease like mice lacking Clc7. However, their osteopetrosis was milder, and they lacked a coat color phenotype. Weinert et al. (2010) concluded that only some roles of ClC7 Cl-/H+ exchange can be taken over by a chloride conductance. This conductance was even deleterious in Clcn7/unc heterozygote mice. Clcn7-null and Clcn7(unc/unc) mice accumulated less chloride in lysosomes than did wildtype mice. Weinert et al. (2010) concluded that lowered lysosomal chloride may underlie their common phenotypes. </p><p>Nicoli et al. (2019) generated mice with a knock-in of Clcn7 Y713C, the variant orthologous to the human CLCN7 Y715C variant (602727.0007), and observed recapitulation of the human phenotype, including striking hair hypopigmentation; dermal fibroblasts with enlarged cytoplasmic vacuoles; lysosomal storage with intracellular vacuoles in the liver, spleen, and kidneys; brain myelination abnormalities; and enlarged cytoplasmic vacuoles in dermal fibroblasts that partially stained for Lamp1 (153330). Tibial sections from mutant mice revealed no osteopetrosis and showed an intact marrow cavity and normally organized trabecular and cortical structure. </p><p>Pressey et al. (2010) studied the neurologic phenotype of a Clcn7 knockout mouse model. The mutant mice had atrophy image of the cortex, corpus callosum, internal capsule, and cerebral peduncles at 4 weeks of age. The mouse brains also had early-onset and progressive astrocytosis of the thalamus and cortex. Microglial activation was identified in the same regions as the astrocytosis. There was also storage of carbohydrate material in neuronal lysosomes throughout the cortex and thalamus. </p>
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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>7 Selected Examples):</strong>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4</strong>
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<span class="mim-text-font">
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CLCN7, GLN555TER
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<br />
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SNP: rs121434432,
|
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ClinVar: RCV000007263
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with autosomal recessive infantile malignant osteopetrosis (OPTB4; 611490), Kornak et al. (2001) identified compound heterozygosity for 2 mutations in the CLCN7 gene: a C-to-T transition in exon 18, leading to a gln555-to-ter substitution, and a 2285G-A transition in exon 24, leading to an arg762-to-gln (R762Q; 602727.0002) substitution. The R762Q substitution abolished a positive charge within the conserved CBS2 domain of CCLN7. To investigate whether the mutations affected protein expression, fibroblasts were analyzed by Western blot analysis and immunofluorescence. In contrast to control cells, CLCN7 protein could not be detected in the fibroblasts from the patient. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4</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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CLCN7, ARG762GLN
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<br />
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SNP: rs121434433,
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gnomAD: rs121434433,
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ClinVar: RCV000007264
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>For discussion of the arg762-to-gln (R762Q) mutation that was identified in a patient with autosomal recessive osteopetrosis-4 (OPTB4; 611490) by Kornak et al. (2001), see 602727.0001. </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 OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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CLCN7, LEU766PRO
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<br />
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SNP: rs121434434,
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ClinVar: RCV000007265
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a girl with autosomal recessive infantile malignant osteopetrosis (OPTB4; 611490), born to second-cousin parents of Chinese ancestry, Cleiren et al. (2001) identified homozygosity for a T-to-C transition at codon 766 of the CLCN7 gene, leading to a leu766-to-pro (L766P) substitution. The substitution was located in the D13 stretch of the conserved CBS2 domain. The asymptomatic parents were heterozygous for the mutation, which was not found in 100 control chromosomes. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 OSTEOPETROSIS, AUTOSOMAL DOMINANT 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CLCN7, ARG767TRP
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<br />
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|
|
SNP: rs121434435,
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|
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ClinVar: RCV000007266, RCV000055846, RCV001851716
|
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a French family and an American family with autosomal dominant osteopetrosis (OPTA2; 166600), previously studied by Benichou et al. (2001) and Yoneyama et al. (1992), respectively, Cleiren et al. (2001) identified heterozygosity for a C-to-T transition at codon 767 of the CLCN7 gene, leading to an arg767-to-trp (R767W) substitution. The substitution abolished a positive charge within the conserved CBS2 domain of CLCN7. Analysis of microsatellite markers indicated that the mutation arose independently in each family. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 OSTEOPETROSIS, AUTOSOMAL DOMINANT 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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CLCN7, 2-BP DEL, 2423AG
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<br />
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|
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SNP: rs2142364275,
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|
|
ClinVar: RCV001899493, RCV002279772, RCV003147692
|
|
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|
|
</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French family and an American family with autosomal dominant osteopetrosis (OPTA2; 166600), Cleiren et al. (2001) identified heterozygosity for a dinucleotide deletion (2423delAG) in the C-terminal portion of CLCN7. The mutation was predicted to generate a frameshift and result in substitutions for the last 10 amino acids of the protein. The French family had previously been reported by Benichou et al. (2001). Analysis of microsatellite markers indicated that the mutation arose independently in each family. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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|
</div>
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|
</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
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CLCN7, ILE261PHE
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<br />
|
|
|
|
SNP: rs121434436,
|
|
|
|
|
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|
|
ClinVar: RCV000007268
|
|
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|
|
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</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Chinese sister and brother with malignant osteopetrosis (OPTB4; 611490), born of first-cousin parents, Lam et al. (2007) identified homozygosity for a c.781A-T transversion in exon 9 of the CLCN7 gene, resulting in an ile261-to-phe (I261F) substitution. Their unaffected parents and an unaffected brother were heterozygous for the mutation, which was not found in 50 Chinese controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPOPIGMENTATION, ORGANOMEGALY, AND DELAYED MYELINATION AND DEVELOPMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLCN7, TYR715CYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057517718,
|
|
|
|
|
|
|
|
ClinVar: RCV000412760, RCV000824813
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 22-month-old Caucasian girl and a 14-month-old Ghanaian boy with hypopigmentation, organomegaly, and delayed myelination and development (HOD; 618541), Nicoli et al. (2019) identified heterozygosity for a de novo c.2144A-G transition (c.2144A-G, NM_001287.5) in exon 23 of the CLCN7 gene, resulting in a tyr715-to-cys (Y715C) substitution at a highly conserved residue within the C-terminal cytoplasmic domain. The mutation was not found in the unaffected parents or in the ExAC, gnomAD, ESP, or EVS databases. Functional analysis of chloride transport in transfected Xenopus oocytes demonstrated an approximately 3-fold increase in outward currents with the Y715C mutant compared to wildtype. Quantitative pH measurements in lysosomes from patient fibroblasts revealed a reduced pH compared to control; increased staining with acidotropic dye confirmed the lowered lysosomal pH. Large, variably sized cytoplasmic single- and double-membraned vacuoles, sometimes containing amorphous material and cellular debris, were present in fibroblasts from both probands, and overexpressing the Y715C variant in control fibroblasts dramatically recapitulated the mutant phenotype of enlarged cytoplasmic vacuoles. Chloroquine treatment of patient dermal fibroblasts increased lysosomal pH in a dose-dependent manner and reduced the abundance of large vacuoles in the mutant cells. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
</div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Benichou, O., Cleiren, E., Gram, J., Bollerslev, J., de Vernejoul, M.-C., Van Hul, W.
|
|
<strong>Mapping of autosomal dominant osteopetrosis type II (Albers-Schonberg disease) to chromosome 16p13.3.</strong>
|
|
Am. J. Hum. Genet. 69: 647-654, 2001.
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|
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|
|
[PubMed: 11468688]
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|
|
[Full Text: https://doi.org/10.1086/323132]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Blair, H. C., Borysenko, C. W., Villa, A., Schlesinger, P. H., Kalla, S. E., Yaroslavsky, B. B., Garcia-Palacios, V., Oakley, J. I., Orchard, P. J.
|
|
<strong>In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects.</strong>
|
|
J. Bone Miner. Res. 19: 1329-1338, 2004.
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|
|
|
|
|
[PubMed: 15231021]
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|
|
[Full Text: https://doi.org/10.1359/JBMR.040403]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brandt, S., Jentsch, T. J.
|
|
<strong>ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family.</strong>
|
|
FEBS Lett. 377: 15-20, 1995.
|
|
|
|
|
|
[PubMed: 8543009]
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|
|
[Full Text: https://doi.org/10.1016/0014-5793(95)01298-2]
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W.
|
|
<strong>Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.</strong>
|
|
Hum. Molec. Genet. 10: 2861-2867, 2001.
|
|
|
|
|
|
[PubMed: 11741829]
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[Full Text: https://doi.org/10.1093/hmg/10.25.2861]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Graves, A. R., Curran, P. K., Smith, C. L., Mindell, J. A.
|
|
<strong>The CI-/H+ antiporter CIC-7 is the primary chloride permeation pathway in lysosomes.</strong>
|
|
Nature 453: 788-792, 2008.
|
|
|
|
|
|
[PubMed: 18449189]
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|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature06907]
|
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Kasper, D., Planells-Cases, R., Fuhrmann, J. C., Scheel, O., Zeitz, O., Ruether, K., Schmitt, A., Poet, M., Steinfeld, R., Schweizer, M., Kornak, U., Jentsch, T. J.
|
|
<strong>Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration.</strong>
|
|
EMBO J. 24: 1079-1091, 2005.
|
|
|
|
|
|
[PubMed: 15706348]
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|
|
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|
|
[Full Text: https://doi.org/10.1038/sj.emboj.7600576]
|
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|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kornak, U., Kasper, D., Bosl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., Jentsch, T. J.
|
|
<strong>Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.</strong>
|
|
Cell 104: 205-215, 2001.
|
|
|
|
|
|
[PubMed: 11207362]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(01)00206-9]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lam, C.-W., Tong, S.-F., Wong, K., Luo, Y. F., Tang, H.-Y., Ha, S.-Y., Chan, M. H.-M.
|
|
<strong>DNA-based diagnosis of malignant osteopetrosis by whole-genome scan using a single-nucleotide polymorphism microarray: standardization of molecular investigations of genetic diseases due to consanguinity.</strong>
|
|
J. Hum. Genet. 52: 98-101, 2007.
|
|
|
|
|
|
[PubMed: 17033731]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10038-006-0075-4]
|
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|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lange, P. F., Wartosch, L., Jentsch, T. J., Fuhrmann, J. C.
|
|
<strong>ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function.</strong>
|
|
Nature 440: 220-223, 2006.
|
|
|
|
|
|
[PubMed: 16525474]
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|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature04535]
|
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nicoli, E.-R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., II, Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., and 15 others.
|
|
<strong>Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification.</strong>
|
|
Am. J. Hum. Genet. 104: 1127-1138, 2019.
|
|
|
|
|
|
[PubMed: 31155284]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2019.04.008]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Pressey, S. N., O'Donnell, K. J., Stauber, T., Fuhrmann, J. C., Tyynela, J., Jentsch, T. J., Cooper, J. D.
|
|
<strong>Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC-6 or ClC-7/Ostm1.</strong>
|
|
J. Neuropath. Exp. Neurol. 69: 1228-1246, 2010.
|
|
|
|
|
|
[PubMed: 21107136]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1097/NEN.0b013e3181ffe742]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Van Hul, W., Van Hul, E., Wuyts, W., Bollerslev, J., Gram, J., Benichou, O., Willems, P. J.
|
|
<strong>The Albers-Schonberg disease (autosomal dominant osteopetrosis) gene is located on chromosome 1p21 in a region containing the macrophage colony stimulating factor (CSF-1) gene. (Abstract)</strong>
|
|
Medizinische Genetik 9: 8 only, 1997.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Weinert, S., Jabs, S., Supanchart, C., Schweizer, M., Gimber, N., Richter, M., Rademann, J., Stauber, T., Kornak, U., Jentsch, T. J.
|
|
<strong>Lysosomal pathology and osteopetrosis upon loss of H(+)-driven lysosomal Cl- accumulation.</strong>
|
|
Science 328: 1401-1403, 2010.
|
|
|
|
|
|
[PubMed: 20430974]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1188072]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yoneyama, T., Fowler, H. L., Pendleton, J. W., Sforza, P. P., Gerard, R. D., Lui, C. Y., Eldridge, T. H., Iranmanesh, A.
|
|
<strong>Elevated serum levels of creatine kinase BB in autosomal dominant osteopetrosis type II--a family study.</strong>
|
|
Clin. Genet. 42: 39-42, 1992.
|
|
|
|
|
|
[PubMed: 1516225]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.1992.tb03134.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
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Hilary J. Vernon - updated : 08/30/2024<br>Marla J. F. O'Neill - updated : 08/15/2019<br>Bao Lige - updated : 09/18/2018<br>Marla J. F. O'Neill - updated : 09/04/2018<br>Ada Hamosh - updated : 6/30/2010<br>Ada Hamosh - updated : 7/9/2008<br>Marla J. F. O'Neill - updated : 10/3/2007<br>Victor A. McKusick - updated : 9/4/2007<br>Ada Hamosh - updated : 12/6/2006<br>George E. Tiller - updated : 10/14/2002<br>Stylianos E. Antonarakis - updated : 1/29/2001
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Rebekah S. Rasooly : 6/17/1998
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carol : 08/30/2024<br>carol : 02/22/2022<br>alopez : 08/15/2019<br>carol : 09/19/2018<br>mgross : 09/18/2018<br>carol : 09/04/2018<br>carol : 05/26/2015<br>alopez : 7/1/2010<br>terry : 6/30/2010<br>wwang : 7/15/2008<br>terry : 7/9/2008<br>carol : 2/19/2008<br>carol : 10/3/2007<br>alopez : 9/6/2007<br>terry : 9/4/2007<br>wwang : 6/6/2007<br>alopez : 12/15/2006<br>terry : 12/6/2006<br>tkritzer : 3/10/2003<br>tkritzer : 3/7/2003<br>cwells : 10/16/2002<br>cwells : 10/16/2002<br>cwells : 10/14/2002<br>mgross : 1/29/2001<br>psherman : 6/18/1998<br>psherman : 6/18/1998
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