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Entry
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- *605427 - TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4
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- OMIM
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<p>
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<span class="h4">*605427</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605427">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000111199;t=ENST00000261740" 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=59341" 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=605427" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000111199;t=ENST00000261740" 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_001177428,NM_001177431,NM_001177433,NM_021625,NM_147204,XM_011538630,XM_011538631,XM_011538632,XM_011538633,XM_011538634,XM_011538635,XM_017019774,XM_047429293,XM_047429294,XM_047429295,XM_047429296" 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_021625" 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=605427" 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=05667&isoform_id=05667_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/TRPV4" 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/10304081,11055322,14582398,15822825,15986275,17894661,22035739,22036052,22547180,22547184,27877102,62901470,70609366,70609368,70609370,109659096,119618284,119618285,219517787,294459965,294459971,294459977,767975026,1034580996,1034580998,1034581000,1034581002,1034581004,1034581006,2217290362,2217290365,2217290368,2217290371,2462533512,2462533514,2462533516,2462533518,2462533520,2462533522,2462533524,2462533526,2462533528,2462533530,2462533532" 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/Q9HBA0" 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=59341" 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=ENSG00000111199;t=ENST00000261740" 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=TRPV4" 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=TRPV4" 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+59341" 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/TRPV4" 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:59341" 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/59341" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr12&hgg_gene=ENST00000261740.7&hgg_start=109783087&hgg_end=109833398&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:18083" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605427[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=605427[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/TRPV4/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/ENSG00000111199" 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=TRPV4" 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=TRPV4" 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=TRPV4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TRPV4&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/PA38293" 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:18083" 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/FBgn0036414.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:1926945" 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/TRPV4#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:1926945" 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/59341/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/OMIA000319/" 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=59341" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003839;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003839 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003841;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003841 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003889;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003889 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030912-7" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:59341" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=TRPV4&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> 111304003, 22764001, 230248006, 717010007, 717264003, 719204007, 722210007, 763067000<br />
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<strong>ICD10CM:</strong> G12.1<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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605427
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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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TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4
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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">
|
|
VANILLOID RECEPTOR-RELATED OSMOTICALLY ACTIVATED CHANNEL; VROAC<br />
|
|
OSM9-LIKE TRANSIENT RECEPTOR POTENTIAL CHANNEL 4; OTRPC4<br />
|
|
TRANSIENT RECEPTOR POTENTIAL CHANNEL 12; TRP12<br />
|
|
TRANSIENT RECEPTOR POTENTIAL, DROSOPHILA, HOMOLOG OF, 12
|
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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=TRPV4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TRPV4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/793?start=-3&limit=10&highlight=793">12q24.11</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:109783087-109833398&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">12:109,783,087-109,833,398</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617383,613508,113500,606835,606071,156530,600175,168400,181405,184095,184252" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="11">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/793?start=-3&limit=10&highlight=793">
|
|
12q24.11
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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?Avascular necrosis of femoral head, primary, 2
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<a href="/entry/617383"> 617383 </a>
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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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[Sodium serum level QTL 1]
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<a href="/entry/613508"> 613508 </a>
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Brachyolmia type 3
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<a href="/entry/113500"> 113500 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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 class="mim-font">
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Digital arthropathy-brachydactyly, familial
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<span class="mim-font">
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<a href="/entry/606835"> 606835 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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Hereditary motor and sensory neuropathy, type IIc
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<span class="mim-font">
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<a href="/entry/606071"> 606071 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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 class="mim-font">
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Metatropic dysplasia
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<span class="mim-font">
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<a href="/entry/156530"> 156530 </a>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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 class="mim-font">
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Neuronopathy, distal hereditary motor, autosomal dominant 8
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<span class="mim-font">
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<a href="/entry/600175"> 600175 </a>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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 class="mim-font">
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Parastremmatic dwarfism
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<span class="mim-font">
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<a href="/entry/168400"> 168400 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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 class="mim-font">
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Scapuloperoneal spinal muscular atrophy
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<td>
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<span class="mim-font">
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<a href="/entry/181405"> 181405 </a>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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 class="mim-font">
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SED, Maroteaux type
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<span class="mim-font">
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<a href="/entry/184095"> 184095 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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<tr>
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<span class="mim-font">
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Spondylometaphyseal dysplasia, Kozlowski type
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/184252"> 184252 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/605427" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/605427" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<br />
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The TRPV4 cation channel mediates calcium influx in response to physical, chemical, and hormonal stimuli in ciliated epithelial cells (<a href="#27" class="mim-tip-reference" title="Lorenzo, I. M., Liedtke, W., Sanderson, M. J., Valverde, M. A. <strong>TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells.</strong> Proc. Nat. Acad. Sci. 105: 12611-12616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18719094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18719094</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18719094[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803970105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18719094">Lorenzo et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18719094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, <a href="#26" class="mim-tip-reference" title="Liedtke, W., Choe, Y., Marti-Renom, M. A., Bell, A. M., Denis, C. S., Sali, A., Hudspeth, A. J., Friedman, J. M., Heller, S. <strong>Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.</strong> Cell 103: 525-535, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11081638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11081638</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11081638[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/s0092-8674(00)00143-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11081638">Liedtke et al. (2000)</a> isolated cDNAs encoding the vanilloid receptor (VR1; <a href="/entry/602076">602076</a>)-related osmotically activated channel, or VROAC, from rat, mouse, human, and chicken. The predicted 872-amino acid VROAC protein has a structure similar to VR1 and VR-like receptor-1 (VRL1, or TRPV2; <a href="/entry/606676">606676</a>), with 6 predicted membrane-spanning domains and a putative pore loop. The N-terminal domain of VROAC bears 3 ankyrin repeats and, like its C terminus, is predicted to occur intracellularly. VROAC is a cation-selective channel that is gated by exposure to hypotonicity within the physiologic range. Northern blot analysis of rat tissues detected abundant expression of a 3.2-kb transcript in kidney, lung, spleen, testis, and fat, with lower expression in sensory ganglia. In situ hybridization showed that in the central nervous system, VROAC is expressed in neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. VROAC was also expressed in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11081638" 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="#37" class="mim-tip-reference" title="Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., Plant, T. D. <strong>OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.</strong> Nature Cell. Biol. 2: 695-702, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11025659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11025659</a>] [<a href="https://doi.org/10.1038/35036318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11025659">Strotmann et al. (2000)</a> also cloned VROAC, which they termed OTRPC4 due to its similarity to other members of the Osm9 subfamily of transient receptor potential channels (e.g., VR1). In situ hybridization analysis revealed transcripts in the inner cortex and a punctate distribution in the outer cortex of mouse kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11025659" 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="#43" class="mim-tip-reference" title="Wissenbach, U., Bodding, M., Freichel, M., Flockerzi, V. <strong>Trp12, a novel Trp related protein from kidney</strong> FEBS Lett. 485: 127-134, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11094154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11094154</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)02212-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11094154">Wissenbach et al. (2000)</a> also cloned VROAC, which they called TRP12. The human protein is 96% identical to the mouse protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11094154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemical analysis, <a href="#27" class="mim-tip-reference" title="Lorenzo, I. M., Liedtke, W., Sanderson, M. J., Valverde, M. A. <strong>TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells.</strong> Proc. Nat. Acad. Sci. 105: 12611-12616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18719094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18719094</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18719094[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803970105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18719094">Lorenzo et al. (2008)</a> detected Trpv4 in mouse ciliated tracheal epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18719094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F. <strong>Mutations in TRPV4 cause an inherited arthropathy of hands and feet.</strong> Nature Genet. 43: 1142-1146, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964574</a>] [<a href="https://doi.org/10.1038/ng.945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964574">Lamande et al. (2011)</a> analyzed Trpv4 expression in mice and observed that localization and expression are similar in knee and phalangeal joints. In the growth plate, Trpv4 was most highly expressed in the proliferative zone, whereas it was downregulated as chondrocytes matured in the prehypertrophic zone and was not detectable by immunohistochemistry in hypertrophic chondrocytes. Trpv4 was expressed at comparable levels in proliferative and articular chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964574" 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="#43" class="mim-tip-reference" title="Wissenbach, U., Bodding, M., Freichel, M., Flockerzi, V. <strong>Trp12, a novel Trp related protein from kidney</strong> FEBS Lett. 485: 127-134, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11094154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11094154</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)02212-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11094154">Wissenbach et al. (2000)</a> determined that the TRPV4 gene contains 15 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11094154" 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 genomic sequence analysis, <a href="#26" class="mim-tip-reference" title="Liedtke, W., Choe, Y., Marti-Renom, M. A., Bell, A. M., Denis, C. S., Sali, A., Hudspeth, A. J., Friedman, J. M., Heller, S. <strong>Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.</strong> Cell 103: 525-535, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11081638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11081638</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11081638[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/s0092-8674(00)00143-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11081638">Liedtke et al. (2000)</a> mapped the TRPV4 gene to chromosome 12q24.1. They mapped the mouse Trpv4 gene to distal chromosome 5 by radiation hybrid analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11081638" 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="#43" class="mim-tip-reference" title="Wissenbach, U., Bodding, M., Freichel, M., Flockerzi, V. <strong>Trp12, a novel Trp related protein from kidney</strong> FEBS Lett. 485: 127-134, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11094154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11094154</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)02212-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11094154">Wissenbach et al. (2000)</a> found that hypoosmotic conditions rapidly activated TRP12, while hyperosmotic conditions inhibited the activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11094154" 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="#37" class="mim-tip-reference" title="Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., Plant, T. D. <strong>OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.</strong> Nature Cell. Biol. 2: 695-702, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11025659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11025659</a>] [<a href="https://doi.org/10.1038/35036318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11025659">Strotmann et al. (2000)</a> showed that OTRPC4 was responsive to changes in extracellular osmolarity in the physiologically relevant range and was expressed in tissues exposed to changing osmotic environments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11025659" 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="#41" class="mim-tip-reference" title="Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., Nilius, B. <strong>Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.</strong> Nature 424: 434-438, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879072</a>] [<a href="https://doi.org/10.1038/nature01807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879072">Watanabe et al. (2003)</a> demonstrated that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome p450 epoxygenase (<a href="/entry/601258">601258</a>)-dependent formation of epoxyeicosatrienoic acids. Application of 5-prime,6-prime-epoxyeicosatrienoic acid at submicromolar concentrations activated TRPV4 in a membrane-delimited manner and caused calcium influx through TRPV4-like channels in vascular endothelial cells. <a href="#41" class="mim-tip-reference" title="Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., Nilius, B. <strong>Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.</strong> Nature 424: 434-438, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879072</a>] [<a href="https://doi.org/10.1038/nature01807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879072">Watanabe et al. (2003)</a> concluded that activation of TRPV4 in vascular endothelial cells might contribute to the relaxant effects of endocannabinoids and their p450 epoxygenase-dependent metabolites on vascular tone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12879072" 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="#35" class="mim-tip-reference" title="Sidhaye, V. K., Guler, A. D., Schweitzer, K. S., D'Alessio, F., Caterina, M. J., King, L. S. <strong>Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.</strong> Proc. Nat. Acad. Sci. 103: 4747-4752, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0511211103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537379">Sidhaye et al. (2006)</a> observed a dose-responsive decrease in Aqp5 (<a href="/entry/600442">600442</a>) abundance in mouse lung epithelial cells exposed to hypotonic medium. Hypotonic reduction of Aqp5 was augmented and reduced, respectively, by conditions that activated or inhibited Trpv4. Hypotonic reduction of Aqp5 required extracellular calcium and was associated with increased intracellular calcium. The response to hypotonicity was recapitulated by coexpression of TRPV4 and AQP5 in human embryonic kidney cells. <a href="#35" class="mim-tip-reference" title="Sidhaye, V. K., Guler, A. D., Schweitzer, K. S., D'Alessio, F., Caterina, M. J., King, L. S. <strong>Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.</strong> Proc. Nat. Acad. Sci. 103: 4747-4752, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0511211103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537379">Sidhaye et al. (2006)</a> concluded that AQP5 abundance is tightly controlled along a spectrum of extracellular osmolalities and that its abundance in hypotonic conditions can be regulated by TRPV4 activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16537379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunofluorescence analysis, <a href="#17" class="mim-tip-reference" title="Gevaert, T., Vriens, J., Segal, A., Everaerts, W., Roskams, T., Talavera, K., Owsianik, G., Liedtke, W., Daelemans, D., Dewachter, I., Van Leuven, F., Voets, T., De Ridder, D., Nilius, B. <strong>Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.</strong> J. Clin. Invest. 117: 3453-3462, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17948126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17948126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17948126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI31766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17948126">Gevaert et al. (2007)</a> detected Trpv4 expression in mouse and rat urothelium and vascular endothelium, but not in other bladder cell types. By measuring intracellular Ca(2+), they found that mouse urothelial cells displayed a Trpv4-dependent response to phorbol esters and to hypotonic cell swelling. <a href="#17" class="mim-tip-reference" title="Gevaert, T., Vriens, J., Segal, A., Everaerts, W., Roskams, T., Talavera, K., Owsianik, G., Liedtke, W., Daelemans, D., Dewachter, I., Van Leuven, F., Voets, T., De Ridder, D., Nilius, B. <strong>Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.</strong> J. Clin. Invest. 117: 3453-3462, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17948126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17948126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17948126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI31766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17948126">Gevaert et al. (2007)</a> concluded that TRPV4 has a role in bladder function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17948126" 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>The rate of mucociliary clearance in the airways is a function of ciliary beat frequency. <a href="#27" class="mim-tip-reference" title="Lorenzo, I. M., Liedtke, W., Sanderson, M. J., Valverde, M. A. <strong>TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells.</strong> Proc. Nat. Acad. Sci. 105: 12611-12616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18719094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18719094</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18719094[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803970105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18719094">Lorenzo et al. (2008)</a> found that tracheal cells from wildtype mice, but not those from Trpv4 -/- mice, increased intracellular Ca(2+) concentration and ciliary beat frequency in response to chemical activation, mildly increased temperature, and ATP application. Both mutant and wildtype cells increased ciliary beat frequency in response to high viscosity solutions. <a href="#27" class="mim-tip-reference" title="Lorenzo, I. M., Liedtke, W., Sanderson, M. J., Valverde, M. A. <strong>TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells.</strong> Proc. Nat. Acad. Sci. 105: 12611-12616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18719094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18719094</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18719094[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803970105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18719094">Lorenzo et al. (2008)</a> concluded that TRPV4 in tracheal epithelial cells transduces physical and chemical stimuli into a Ca(2+) signal that regulates ciliary beat frequency and mucociliary transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18719094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> found low levels of TRPV4 expression in human dorsal and ventral spinal cords, at approximately 95% lower levels compared to tracheal cartilage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20037586" 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="#36" class="mim-tip-reference" title="Sonkusare, S. K., Bonev, A. D., Ledoux, J., Liedtke, W., Kotlikoff, M. I., Heppner, T. J., Hill-Eubanks, D. C., Nelson, M. T. <strong>Elementary Ca(2+) signals through endothelial TRPV4 channels regulate vascular function.</strong> Science 336: 597-601, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22556255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22556255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22556255[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/10.1126/science.1216283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22556255">Sonkusare et al. (2012)</a> identified local calcium ion signals, which they called sparklets, in the vascular endothelium of resistance arteries that represent calcium ion influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a 4-channel cluster was cooperative, with activation of as few as 3 channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small-conductance (SK) calcium ion-sensitive potassium channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. <a href="#36" class="mim-tip-reference" title="Sonkusare, S. K., Bonev, A. D., Ledoux, J., Liedtke, W., Kotlikoff, M. I., Heppner, T. J., Hill-Eubanks, D. C., Nelson, M. T. <strong>Elementary Ca(2+) signals through endothelial TRPV4 channels regulate vascular function.</strong> Science 336: 597-601, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22556255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22556255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22556255[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/10.1126/science.1216283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22556255">Sonkusare et al. (2012)</a> concluded that their results supported the concept that calcium ion influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high calcium ion sensitivity of IK and SK channels to cause vasodilation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22556255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using various methods, <a href="#23" class="mim-tip-reference" title="Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E. <strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations.</strong> Hum. Molec. Genet. 21: 2166-2180, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22328087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22328087</a>] [<a href="https://doi.org/10.1093/hmg/dds032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22328087">Lanciotti et al. (2012)</a> found that MLC1 (<a href="/entry/605908">605908</a>), TRPV4, HEPACAM (<a href="/entry/611642">611642</a>), syntrophin (see <a href="/entry/601017">601017</a>), caveolin-1 (CAV1; <a href="/entry/601047">601047</a>), Kir4.1 (KCNJ10; <a href="/entry/602208">602208</a>), and AQP4 (<a href="/entry/600308">600308</a>) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; <a href="/entry/182330">182330</a>), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22328087" 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>Skeletal Disorders</em></strong></p><p>
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<a href="#34" class="mim-tip-reference" title="Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. <strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong> Nature Genet. 40: 999-1003, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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/ng.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587396">Rock et al. (2008)</a> identified missense mutations in the TRPV4 gene in 2 families segregating autosomal dominant brachyolmia (BCYM3; <a href="/entry/113500">113500</a>). Expression of the R616Q mutation (<a href="#0001">605427.0001</a>) in human embryonic kidney cells yielded a much larger constitutive current before agonist application. The shape of the IV curve and the reversal potentials were not changed. <a href="#34" class="mim-tip-reference" title="Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. <strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong> Nature Genet. 40: 999-1003, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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/ng.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587396">Rock et al. (2008)</a> demonstrated significantly increased constitutively activated current in the mutant. Similar data were obtained for the mutation encoding V620I (<a href="#0002">605427.0002</a>), with a significantly increased constitutive current at +100 mV, albeit somewhat less increased than for the R616Q mutant. Thus, both missense mutations conferred a gain-of-function phenotype by significantly increasing the fraction of constitutively open channels and by potentiating agonist activation. <a href="#34" class="mim-tip-reference" title="Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. <strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong> Nature Genet. 40: 999-1003, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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/ng.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587396">Rock et al. (2008)</a> suggested that the data presented in their paper contributed to evidence that TRPV4 is a key regulatory molecule in the growth plate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; <a href="/entry/184252">184252</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified heterozygous mutations in the TRPV4 gene. Four of the patients had an R594H mutation (<a href="#0003">605427.0003</a>) in the cytoplasmic S4 domain, which is associated with increased intracellular calcium ion concentration and activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified heterozygous missense mutations in the TRPV4 gene: I331F (<a href="#0006">605427.0006</a>) in the ankyrin-5 domain and a cytoplasmic mutation (P799L; <a href="#0007">605427.0007</a>). Both mutations occurred de novo. Because mutations in the TRPV4 gene produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal dominant brachyolmia to Kozlowski-type SMD to autosomal dominant metatropic dysplasia, <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> suggested that these disorders should be grouped into a new bone dysplasia family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" 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="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> analyzed the TRPV4 gene in 22 MTD probands and 20 SMDK probands, and identified heterozygous TRPV4 mutations in all, except for 1 MTD proband. In the MTD patients, the recurrent P799L mutation was found in 9 patients, and 4 more patients had 3 different substitutions at the pro799 codon (<a href="#0013">605427.0013</a>-<a href="#0015">605427.0015</a>). The remaining 8 MTD patients included 7 with novel missense mutations and 1 with a 3-bp deletion of a codon (F471del; <a href="#0016">605427.0016</a>), which the authors stated was the first mutation other than a missense mutation to be reported in the TRPV4 gene. In the SMDK patients, the recurrent R594H mutation was found in 12 patients, and 8 had novel missense mutations (see, e.g., <a href="#0017">605427.0017</a> and <a href="#0018">605427.0018</a>). <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> designated pro799 in exon 15 of the TRPV4 gene as a 'hot codon' for MTD mutations and arg594 in exon 11 as a hotspot for SMDK mutations. <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> noted that although some radiologic signs are shared by both disorders, the presence or absence of dumbbell-shaped femurs ascertained distinction between MTD and SMDK, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 patients with the Maroteaux type of spondyloepiphyseal dysplasia (<a href="/entry/184095">184095</a>), <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygous mutations in the TRPV4 gene (see, e.g., <a href="#0019">605427.0019</a>-<a href="#0021">605427.0021</a>), 2 of which had previously been identified in patients with MTD (<a href="#0007">605427.0007</a>) and SMDK (<a href="#0018">605427.0018</a>). In a patient with parastremmatic dwarfism (<a href="/entry/168400">168400</a>), they identified heterozygosity for a missense mutation in TRPV4 (R594H; <a href="#0003">605427.0003</a>) that had previously been found in patients with SMDK (<a href="/entry/184252">184252</a>). <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> noted that genotype/phenotype correlations did not appear to be robust, and suggested that in the presence of a TRPV4 mutation, modulation of the clinical phenotype by other genes and/or by nongenetic factors might occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> reported 10 patients with varying severity of metatropic dysplasia, all of whom carried a heterozygous mutation in the TRPV4 gene (see, e.g., <a href="#0006">605427.0006</a>-<a href="#0007">605427.0007</a>, <a href="#0023">605427.0023</a>-<a href="#0024">605427.0024</a>). Five patients had a lethal form of the disorder with death in the neonatal period or infancy, whereas 5 had a nonlethal disorder classified as mild, moderately severe, or severe. There was no clear relationship between the severity of the disorder and type of mutation or domain affected, but <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> suggested that the degree of constitutive activation of the mutant channels likely correlates with disease severity. Histologic studies of bone derived from 2 lethal cases showed abnormally thick cartilage with nodular proliferation, short diaphyses, and abnormal bone formation, indicating disrupted endochondral ossification. There was also evidence of abnormal chondrogenesis and abnormal differentiation of mesenchymal progenitors as well as lack of normal columns of chondrocytes. <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> suggested that the mechanism of disease may result from increased calcium in chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" 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="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> reported 4 patients, including a pair of monozygotic twins, with a severe lethal form of metatropic dysplasia associated with fetal akinesia. Three of the 4 were found to have absent movements, severe contractures, and features of metatropic dysplasia on prenatal ultrasound, and the pregnancies were terminated. The fourth patient presented with multiple joint contractures and absent limb movements at birth, consistent with fetal akinesia. Features of severe metatropic dysplasia in these patients included short long bones, cartilaginous joint expansion, narrow thorax, flat vertebral bodies, and sacrococcygeal tail. The fourth patient had a normal neonatal neurologic examination, although movement was restricted, but electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. Genetic analysis of the 4 patients identified 3 different heterozygous de novo missense mutations in the TRPV4 gene (<a href="#0027">605427.0027</a>-<a href="#0029">605427.0029</a>). <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and since electrophysiologic studies of 1 indicated a neuropathic process, these TRPV4 mutations may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 26 patients diagnosed with various skeletal dysplasias, including 15 with MTD, 9 with SMDK, and 2 with brachyolmia, <a href="#3" class="mim-tip-reference" title="Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. <strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong> Orphanet J. Rare Dis. 6: 37, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21658220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21658220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21658220[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/10.1186/1750-1172-6-37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21658220">Andreucci et al. (2011)</a> sequenced the TRPV4 gene and identified heterozygosity for missense mutations in 21 of them, including 14 patients with a diagnosis of MTD and 7 patients with SMDK (see, e.g., <a href="#0003">605427.0003</a>, <a href="#0007">605427.0007</a>, <a href="#0014">605427.0014</a>). In addition, 1 patient (case 17) with SMDK was heterozygous for a 3-bp duplication (L523dup). The 4 patients in whom no mutation was detected in the TRPV4 gene all exhibited atypical features for their respective clinical diagnoses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21658220" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, <a href="#18" class="mim-tip-reference" title="Grigelioniene, G., Geiberger, S., Horemuzova, E., Mostrom, E., Jantti, N., Neumeyer, L., Astrom, E., Nordenskjold, M., Nordgren, A., Makitie, O. <strong>Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course.</strong> Am. J. Med. Genet. 164A: 1635-1641, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24677493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24677493</a>] [<a href="https://doi.org/10.1002/ajmg.a.36502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24677493">Grigelioniene et al. (2014)</a> identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene (<a href="#0001">605427.0001</a>), which segregated fully with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24677493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 sibs from a Greek family with avascular necrosis of the femoral head (ANFH2; <a href="/entry/617383">617383</a>), <a href="#28" class="mim-tip-reference" title="Mah, W., Sonkusare, S. K., Wang, T., Azeddine, B., Pupavac, M., Carrot-Zhang, J., Hong, K., Majewski, J., Harvey, E. J., Russell, L., Chalk, C., Rosenblatt, D. S., Nelson, M. T., Seguin, C. <strong>Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.</strong> J. Med. Genet. 53: 705-709, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27330106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27330106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27330106[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/10.1136/jmedgenet-2016-103829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27330106">Mah et al. (2016)</a> identified heterozygosity for a truncating mutation in the TRPV4 gene (V829WfsX3; <a href="#0034">605427.0034</a>). The mutation was not found in an unaffected brother or in public variant databases, but DNA from the sibs' parents was unavailable for study. Functional analysis in patient fibroblasts and transduced HEK293 cells indicated that the mutation results in a gain of function of TRPV4 channels by impeding channel closure. <a href="#28" class="mim-tip-reference" title="Mah, W., Sonkusare, S. K., Wang, T., Azeddine, B., Pupavac, M., Carrot-Zhang, J., Hong, K., Majewski, J., Harvey, E. J., Russell, L., Chalk, C., Rosenblatt, D. S., Nelson, M. T., Seguin, C. <strong>Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.</strong> J. Med. Genet. 53: 705-709, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27330106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27330106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27330106[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/10.1136/jmedgenet-2016-103829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27330106">Mah et al. (2016)</a> noted that only 2 of the previously reported TRPV4 mutations are truncating, and none are located beyond residue 799. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27330106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with nonlethal MTD, <a href="#42" class="mim-tip-reference" title="Weinstein, M. M., Kang, T., Lachman, R. S., Bamshad, M., Nickerson, D. A., Krakow, D., Cohn, D. H. <strong>Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 170A: 3298-3302, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27530454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27530454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27530454[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/10.1002/ajmg.a.37942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27530454">Weinstein et al. (2016)</a> identified somatic mosaicism for a leu618-to-pro substitution (L618P; <a href="#0035">605427.0035</a>) in the TRPV4 gene that had previously been identified in heterozygosity by <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> in a patient with lethal MTD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27530454+20425821" 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>Neuromuscular Disorders</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous mutation in the TRPV4 gene (R315W; <a href="#0008">605427.0008</a>). Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; <a href="/entry/606071">606071</a>), 1 had congenital spinal muscular atrophy (HMND8; <a href="/entry/600175">600175</a>), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; <a href="/entry/181405">181405</a>). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (originally reported by <a href="#29" class="mim-tip-reference" title="McEntagart, M. E., Reid, S. L., Irrthum, A., Douglas, J. B., Eyre, K. E. D., Donaghy, M. J., Anderson, N. E., Rahman, N. <strong>Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24.</strong> Ann. Neurol. 57: 293-297, 2005. Note: Erratum: Ann. Neurol. 57: 609 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668982</a>] [<a href="https://doi.org/10.1002/ana.20375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668982">McEntagart et al., 2005</a>). <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> identified 2 additional TRPV4 mutations (R269H, <a href="#0009">605427.0009</a> and R316C, <a href="#0010">605427.0010</a>) in affected members of 3 additional families with these 3 phenotypes, indicating that they are allelic disorders. All 3 mutations occurred at the outer helices of the ANK4 and ANK5 domains, in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression, as well as an impaired response to stimulus-dependent channel activity. These studies suggested that the mutations interfered with normal channel trafficking and function, resulting in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15668982+20037588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Independently, <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> and <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> identified some of the same mutations as <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> in additional families with either SPSMA or HMSN2C, including the original families reported with the disorders (<a href="#11" class="mim-tip-reference" title="DeLong, R., Siddique, T. <strong>A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features.</strong> Arch. Neurol. 49: 905-908, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1520078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1520078</a>] [<a href="https://doi.org/10.1001/archneur.1992.00530330027010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1520078">Delong and Siddique, 1992</a> and <a href="#14" class="mim-tip-reference" title="Dyck, P. J., Litchy, W. J., Minnerath, S., Bird, T. D., Chance, P. F., Schaid, D. J., Aronson, A. E. <strong>Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis.</strong> Ann. Neurol. 35: 608-615, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8179305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8179305</a>] [<a href="https://doi.org/10.1002/ana.410350515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8179305">Dyck et al., 1994</a>, respectively). <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> identified a novel mutation (R269C; <a href="#0011">605427.0011</a>) in the same protein region in another family with HMSN2C. In contrast to <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a>, functional studies by <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> and <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> indicated that the mutant proteins were trafficked normally, appeared at the plasma membrane, and resulted in increased calcium channel activity consistent with a gain of function. Commenting on the divergent functional findings of <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> and <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> and <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a>, <a href="#31" class="mim-tip-reference" title="Nilius, B., Owsianik, G. <strong>Channelopathies converge on TRPV4.</strong> Nature Genet. 42: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20104247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20104247</a>] [<a href="https://doi.org/10.1038/ng0210-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20104247">Nilius and Owsianik (2010)</a> suggested that the discrepancies were related to differences in experimental protocols. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20037586+20104247+20037587+20037588+1520078+8179305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family and an unrelated patient with CMT2C, <a href="#20" class="mim-tip-reference" title="Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J. <strong>TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.</strong> Neurology 76: 887-894, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21288981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21288981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21288981[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/10.1212/WNL.0b013e31820f2de3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21288981">Klein et al. (2011)</a> identified 2 different heterozygous mutations in the TRPV4 gene (R232C, <a href="#0025">605427.0025</a> and R316H, <a href="#0026">605427.0026</a>, respectively) in conserved residues in the ankyrin-repeat domain. In vitro functional expression studies showed that both mutant proteins had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant proteins caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. <a href="#20" class="mim-tip-reference" title="Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J. <strong>TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.</strong> Neurology 76: 887-894, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21288981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21288981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21288981[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/10.1212/WNL.0b013e31820f2de3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21288981">Klein et al. (2011)</a> concluded that CMT2C-related mutations in this gene cause a dominant gain of function rather than haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21288981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By direct screening of the TRPV4 gene in 169 French patients with inherited axonal sensorimotor or motor peripheral neuropathy, <a href="#15" class="mim-tip-reference" title="Echaniz-Laguna, A., Dubourg, O., Carlier, P., Carlier, R.-Y., Sabouraud, P., Pereon, Y., Chapon, F., Thauvin-Robinet, C., Laforet, P., Eymard, B., Latour, P., Stojkovic, T. <strong>Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy.</strong> Neurology 82: 1919-1926, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24789864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24789864</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24789864">Echaniz-Laguna et al. (2014)</a> identified pathogenic heterozygous mutations in 12 (7%) patients. However, these 12 patients accounted for 16% of 74 patients from the entire cohort who had neuropathy with vocal cord paresis and/or skeletal dysplasia; no mutations were found in 95 patients with pure CMT2. All 12 patients had childhood-onset motor neuropathy with a variety of associated findings, including foot deformities (100%), kyphoscoliosis (100%), increased serum creatine kinase (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Six mutations occurred de novo, and 2 asymptomatic carriers were observed. The diagnoses included dHMN8 (HMND8; <a href="/entry/600175">600175</a>; 7 patients), congenital spinal muscular atrophy with arthrogryposis (2 patients), scapuloperoneal spinal muscular atrophy, and CMT2C. Several of the mutations had previously been reported in patients with a spectrum of axonal neuropathies; functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24789864" 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>Serum Sodium Level Quantitative Trait Locus</em></strong></p><p>
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<a href="#39" class="mim-tip-reference" title="Tian, W., Fu, Y., Garcia-Elias, A., Fernandez-Fernandez, J. M., Vicente, R., Kramer, P. L., Klein, R. F., Hitzemann, R., Orwoll, E. S., Wilmot, B., McWeeney, S., Valverde, M. A., Cohen, D. M. <strong>A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.</strong> Proc. Nat. Acad. Sci. 106: 14034-14039, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19666518[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0904084106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19666518">Tian et al. (2009)</a> demonstrated that the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3742030;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3742030</a> SNP in the TRPV4 gene (P19S; <a href="#0012">605427.0012</a>) was significantly associated with serum sodium concentration (<a href="/entry/613508">613508</a>) and with hyponatremia, defined as serum sodium less than 135 mEq/L, in 2 non-Hispanic Caucasian male populations. In heterologous expression studies in HEK293 cells, P19S mutant channels showed diminished response to hypotonic stress and to the osmotransducing lipid epoxyeicosatrienoic acid compared to wildtype channels. <a href="#39" class="mim-tip-reference" title="Tian, W., Fu, Y., Garcia-Elias, A., Fernandez-Fernandez, J. M., Vicente, R., Kramer, P. L., Klein, R. F., Hitzemann, R., Orwoll, E. S., Wilmot, B., McWeeney, S., Valverde, M. A., Cohen, D. M. <strong>A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.</strong> Proc. Nat. Acad. Sci. 106: 14034-14039, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19666518[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0904084106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19666518">Tian et al. (2009)</a> suggested that the P19S polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19666518" 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>Digital Arthropathy-Brachydactyly</em></strong></p><p>
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In 2 families with digital arthropathy-brachydactyly mapping to chromosome 12q24 (FDAB; <a href="/entry/606835">606835</a>), <a href="#22" class="mim-tip-reference" title="Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F. <strong>Mutations in TRPV4 cause an inherited arthropathy of hands and feet.</strong> Nature Genet. 43: 1142-1146, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964574</a>] [<a href="https://doi.org/10.1038/ng.945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964574">Lamande et al. (2011)</a> sequenced the candidate gene TRPV4 and identified 2 different heterozygous missense mutations that segregated with disease in each family (<a href="#0030">605427.0030</a> and <a href="#0031">605427.0031</a>). In a sporadic patient with digital arthropathy-brachydactyly, heterozygosity for a third missense mutation was identified (<a href="#0032">605427.0032</a>). All 3 arthropathy-associated substitutions are located at highly conserved residues in TRPV4 finger loop 3 and reduce channel activity, in contrast to gain-of-function TRPV4 mutations causing skeletal dysplasias and peripheral neuropathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964574" 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="#38" class="mim-tip-reference" title="Suzuki, M., Mizuno, A., Kodaira, K., Imai, M. <strong>Impaired pressure sensation in mice lacking TRPV4.</strong> J. Biol. Chem. 278: 22664-22668, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12692122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12692122</a>] [<a href="https://doi.org/10.1074/jbc.M302561200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12692122">Suzuki et al. (2003)</a> generated Trpv4-knockout mice by homologous recombination. The Trpv4-null mice showed reduced sensitivity of the tail to pressure and acidic nociception. Their threshold to noxious stimuli and the conduction velocity of myelinated nerve responding to stimuli were impaired, but they retained olfaction, taste sensation, and heat avoidance. The Trpv4 channel expressed in vitro in CHO cells was opened by low pH, citrate, and inflation but not by heat or capsaicin. These data identified the TRPV4 channel as essential for the normal detection of pressure and as a receptor of the high-threshold mechanosensory complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12692122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Gevaert, T., Vriens, J., Segal, A., Everaerts, W., Roskams, T., Talavera, K., Owsianik, G., Liedtke, W., Daelemans, D., Dewachter, I., Van Leuven, F., Voets, T., De Ridder, D., Nilius, B. <strong>Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.</strong> J. Clin. Invest. 117: 3453-3462, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17948126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17948126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17948126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI31766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17948126">Gevaert et al. (2007)</a> found that Trpv4 -/- mice had an incontinent phenotype, with a lower frequency of voiding contractions and a higher frequency of nonvoiding contractions. Relative to controls, explanted bladder strips from Trpv4 -/- mice showed reduced amplitude of spontaneous contractions, and whole bladders from Trpv4 -/- mice showed decreased intravesical stretch-evoked ATP release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17948126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605427[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912632;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=rs121912632" 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=rs121912632" 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=RCV000005280 OR RCV000202519 OR RCV001269634 OR RCV003505079" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005280, RCV000202519, RCV001269634, RCV003505079" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005280...</a>
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<p>In a 5-generation pedigree segregating autosomal dominant brachyolmia type 3 (BCYM3; <a href="/entry/113500">113500</a>), <a href="#34" class="mim-tip-reference" title="Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. <strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong> Nature Genet. 40: 999-1003, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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/ng.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587396">Rock et al. (2008)</a> identified a c.1847G-A transition in the TRPV4 gene, resulting in an arg616-to-gln (R616Q) substitution in the fifth transmembrane region. This change was not present among 107 alleles of ancestry-matched unaffected individuals and was present in heterozygosity in all affected members of the pedigree. The mutation results in a gain of function and constitutive activation of the TRPV4 channel. R616 is conserved among human, rat, mouse, chicken, stickleback, and zebrafish proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, <a href="#18" class="mim-tip-reference" title="Grigelioniene, G., Geiberger, S., Horemuzova, E., Mostrom, E., Jantti, N., Neumeyer, L., Astrom, E., Nordenskjold, M., Nordgren, A., Makitie, O. <strong>Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course.</strong> Am. J. Med. Genet. 164A: 1635-1641, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24677493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24677493</a>] [<a href="https://doi.org/10.1002/ajmg.a.36502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24677493">Grigelioniene et al. (2014)</a> identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene, which segregated fully with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24677493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121912633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912633;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121912633?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121912633" 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=rs121912633" 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=RCV000005281 OR RCV000202464 OR RCV000202535 OR RCV000545248 OR RCV000728663 OR RCV001172890 OR RCV003992145" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005281, RCV000202464, RCV000202535, RCV000545248, RCV000728663, RCV001172890, RCV003992145" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005281...</a>
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<p>In a family segregating autosomal dominant brachyolmia type 3 (BCYM3; <a href="/entry/113500">113500</a>), <a href="#34" class="mim-tip-reference" title="Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. <strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong> Nature Genet. 40: 999-1003, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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/ng.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587396">Rock et al. (2008)</a> identified heterozygosity for an c.858G-A transition in the TRPV4 gene, resulting in a val620-to-ile (V620I) substitution. V620 is conserved among human, rat, mouse, chicken, stickleback, and zebrafish proteins. <a href="#34" class="mim-tip-reference" title="Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. <strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong> Nature Genet. 40: 999-1003, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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/ng.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587396">Rock et al. (2008)</a> found that the V620I substitution results in constitutive activation of the TRPV4 channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs77975504 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77975504;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=rs77975504" 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=rs77975504" 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=RCV000005282 OR RCV000005283 OR RCV000202560 OR RCV000498625 OR RCV000691603 OR RCV001618207 OR RCV002243623 OR RCV002512802" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005282, RCV000005283, RCV000202560, RCV000498625, RCV000691603, RCV001618207, RCV002243623, RCV002512802" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005282...</a>
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<p><strong><em>Spondylometaphyseal Dysplasia, Kozlowski Type</em></strong></p><p>
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In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; <a href="/entry/184252">184252</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified a c.1781G-A transition in exon 11 of the TRPV4 gene, resulting in an arg594-to-his (R594H) substitution in the cytoplasmic S4 domain. In 2 of the 4 families, the mutation was not found in DNA from the unaffected parents, establishing the change as de novo. The mutation was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 12 probands with SMDK, <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for the R594H mutation and concluded that arg594 is a hotspot for mutation in SMDK. One of the patients did not show overt metaphyseal changes on x-ray and was considered to have a phenotype of intermediate severity between SMDK and brachyolmia (<a href="/entry/113500">113500</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" 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>Parastremmatic Dwarfism</em></strong></p><p>
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In a 7-year-old girl with parastremmatic dwarfism (<a href="/entry/168400">168400</a>), <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygosity for the R594H mutation in the TRPV4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503319" 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>Metatropic Dysplasia</em></strong></p><p>
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In a mother and 2 sons (patients 5, 6, and 7) and 2 unrelated patients (10 and 11, previously reported by <a href="#19" class="mim-tip-reference" title="Kannu, P., Aftimos, S., Mayne, V., Donnan, L., Savarirayan, R. <strong>Metatropic dysplasia: clinical and radiologic findings in 11 patients demonstrating long-term natural history.</strong> Am. J. Med. Genet. 143A: 2512-2522, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17879966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17879966</a>] [<a href="https://doi.org/10.1002/ajmg.a.31941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17879966">Kannu et al., 2007</a>) with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#3" class="mim-tip-reference" title="Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. <strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong> Orphanet J. Rare Dis. 6: 37, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21658220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21658220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21658220[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/10.1186/1750-1172-6-37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21658220">Andreucci et al. (2011)</a> identified heterozygosity for the R594H mutation in the TRPV4 gene. <a href="#3" class="mim-tip-reference" title="Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. <strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong> Orphanet J. Rare Dis. 6: 37, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21658220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21658220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21658220[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/10.1186/1750-1172-6-37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21658220">Andreucci et al. (2011)</a> noted that the 2 sons exhibited intrafamilial variability, with one showing radiographic features that were more consistent with MTD and the other showing features more consistent with SMDK. The authors also identified heterozygosity for the R594H variant in 3 unrelated patients (patients 15, 16, and 22) clinically diagnosed with SMDK. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21658220+17879966" 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">rs121912634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912634;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=rs121912634" 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=rs121912634" 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=RCV000005284 OR RCV000202481" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005284, RCV000202481" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005284...</a>
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<p>In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; <a href="/entry/184252">184252</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified heterozygosity for a c.992A-G transition in exon 6 of the TRPV4 gene, resulting in an asp333-to-gly (N333G) substitution in the ankyrin-5 domain. The mutation, which was inherited from the proband's affected mother, was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" 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">rs121912635 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912635;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=rs121912635" 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=rs121912635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with spondylometaphyseal dysplasia of the Kozlowski type (SMDK; <a href="/entry/184252">184252</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified heterozygosity for a c.2146G-T transversion in exon 13 of the TRPV4 gene, resulting in an ala716-to-ser (A716S) substitution in the cytoplasmic S6 domain. The mutation occurred de novo and was not associated with increased basal intracellular calcium ion concentration or intracellular activity when compared with wildtype. The mutation occurs in a highly conserved residue and was not found in at least 214 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121912636 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912636;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121912636?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121912636" 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=rs121912636" 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=RCV000005286 OR RCV000202518" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005286, RCV000202518" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005286...</a>
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<p>In a patient with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified heterozygosity for a c.1080A-T transversion in exon 6 of the TRPV4 gene, resulting in an ile331-to-phe (I331F) substitution in the ankyrin-5 domain. The mutation occurs in a highly conserved residue and was not identified in the unaffected parents or in at least 214 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" 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>Variant Function</em></strong></p><p>
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By in vitro functional expression studies in HEK cells, <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> showed that the I331F-mutant protein had larger basal currents with constitutive open channels compared to wildtype. Treatment with agonists resulted in even larger calcium currents and increased intracellular calcium levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" 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">rs121912637 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912637;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=rs121912637" 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=rs121912637" 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=RCV000005287 OR RCV000005288 OR RCV000202554 OR RCV000624630 OR RCV000707315 OR RCV001253672 OR RCV001311314 OR RCV003388565" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005287, RCV000005288, RCV000202554, RCV000624630, RCV000707315, RCV001253672, RCV001311314, RCV003388565" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005287...</a>
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<p><strong><em>Metatropic Dysplasia</em></strong></p><p>
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In a patient with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#21" class="mim-tip-reference" title="Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. <strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong> Am. J. Hum. Genet. 84: 307-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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.2009.01.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19232556">Krakow et al. (2009)</a> identified heterozygosity for a c.2396C-T transition in exon 15 of the TRPV4 gene, resulting in a pro799-to-leu substitution in the cytoplasmic domain. The mutation, which occurs in a highly conserved residue, was not identified in the unaffected parents or in at least 214 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19232556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 9 probands with MTD, <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for the P799L mutation. Four more MTD patients had 3 different substitutions at pro799 (see <a href="#0013">605427.0013</a>-<a href="#0015">605427.0015</a>), leading <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> to designate it as a 'hot codon' for MTD mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> reported 2 unrelated patients with metatropic dysplasia who were heterozygous for the P799L mutation. Each had a nonlethal but moderately severe form of the disorder, with scoliosis, platyspondyly with irregular endplates, widened irregular metaphyses, and marked epiphyseal delay. In vitro functional expression studies in HEK cells showed that the P799L-mutant protein had larger basal currents with constitutive open channels compared to wildtype. Treatment with agonists resulted in even larger calcium currents and increased intracellular calcium levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 patients with MTD (patients 2, 3, 4, 12, and 13), including 3 patients previously reported by <a href="#19" class="mim-tip-reference" title="Kannu, P., Aftimos, S., Mayne, V., Donnan, L., Savarirayan, R. <strong>Metatropic dysplasia: clinical and radiologic findings in 11 patients demonstrating long-term natural history.</strong> Am. J. Med. Genet. 143A: 2512-2522, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17879966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17879966</a>] [<a href="https://doi.org/10.1002/ajmg.a.31941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17879966">Kannu et al. (2007)</a> (patients 2, 3, and 4), <a href="#3" class="mim-tip-reference" title="Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. <strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong> Orphanet J. Rare Dis. 6: 37, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21658220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21658220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21658220[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/10.1186/1750-1172-6-37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21658220">Andreucci et al. (2011)</a> identified heterozygosity for the P799L variant in the TRPV4 gene. Patients 2 and 3 were a father/daughter pair; the father was originally described by <a href="#6" class="mim-tip-reference" title="Beck, M., Roubicek, M., Rogers, J. G., Naumoff, P., Spranger, J. <strong>Heterogeneity of metatropic dysplasia.</strong> Europ. J. Pediat. 140: 231-237, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6628444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6628444</a>] [<a href="https://doi.org/10.1007/BF00443368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6628444">Beck et al. (1983)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21658220+6628444+17879966" 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>Spondyloepiphyseal Dysplasia, Maroteaux Type</em></strong></p><p>
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In 2 unrelated patients with the Maroteaux type of spondyloepiphyseal dysplasia (<a href="/entry/184095">184095</a>), 1 of whom was a girl previously reported by <a href="#30" class="mim-tip-reference" title="Megarbane, A., Maroteaux, P., Caillaud, C., Le Merrer, M. <strong>Spondyloepimetaphyseal dysplasia of Maroteaux (pseudo-Morquio type II syndrome): report of a new patient and review of the literature.</strong> Am. J. Med. Genet. 125A: 61-66, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14755468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14755468</a>] [<a href="https://doi.org/10.1002/ajmg.a.20442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14755468">Megarbane et al. (2004)</a>, <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygosity for the P799L mutation in the TRPV4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14755468+20503319" 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">rs267607143 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607143;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=rs267607143" 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=rs267607143" 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=RCV000005289 OR RCV000005290 OR RCV000005291 OR RCV000202514 OR RCV000236487 OR RCV000789585 OR RCV002371762 OR RCV003335013 OR RCV004547459" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005289, RCV000005290, RCV000005291, RCV000202514, RCV000236487, RCV000789585, RCV002371762, RCV003335013, RCV004547459" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005289...</a>
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<p><a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous c.943C-T transition in exon 6 of the TRPV4 gene, resulting in an arg315-to-trp (R315W) substitution. Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; <a href="/entry/606071">606071</a>), 1 had distal hereditary motor neuropathy, type VIII (HMND8; <a href="/entry/600175">600175</a>), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; <a href="/entry/181405">181405</a>). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (<a href="#29" class="mim-tip-reference" title="McEntagart, M. E., Reid, S. L., Irrthum, A., Douglas, J. B., Eyre, K. E. D., Donaghy, M. J., Anderson, N. E., Rahman, N. <strong>Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24.</strong> Ann. Neurol. 57: 293-297, 2005. Note: Erratum: Ann. Neurol. 57: 609 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668982</a>] [<a href="https://doi.org/10.1002/ana.20375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668982">McEntagart et al., 2005</a>). The mutation was not found in 304 control individuals. The R315W mutation occurred at the outer helices of the ANK4 and ANK5 domains in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies indicated that the mutation interferes with normal channel trafficking and function. Haploinsufficiency was proposed as the most likely underlying mechanism, although a gain of function could not be fully excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15668982+20037588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Chen, D.-H., Sul, Y., Weiss, M., Hillel, A., Lipe, H., Wolff, J., Matsushita, M., Raskind, W., Bird, T. <strong>CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene.</strong> Neurology 75: 1968-1975, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21115951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21115951</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21115951[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/10.1212/WNL.0b013e3181ffe4bb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21115951">Chen et al. (2010)</a> identified a heterozygous R315W mutation in a 47-year-old mother and her 26-year-old daughter with HMSN2C and vocal cord paresis; the family had originally been reported by <a href="#14" class="mim-tip-reference" title="Dyck, P. J., Litchy, W. J., Minnerath, S., Bird, T. D., Chance, P. F., Schaid, D. J., Aronson, A. E. <strong>Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis.</strong> Ann. Neurol. 35: 608-615, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8179305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8179305</a>] [<a href="https://doi.org/10.1002/ana.410350515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8179305">Dyck et al. (1994)</a>. Both patients had onset in infancy and developed a relatively severe form of distal muscle weakness and distal sensory loss, as well as short stature. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8179305+21115951" 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="#1" class="mim-tip-reference" title="Aharoni, S., Harlalka, G., Offiah, A., Shuper, A., Crosby, A. H., McEntagart, M. <strong>Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorder.</strong> Am. J. Med. Genet. 155A: 3153-3156, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22065612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22065612</a>] [<a href="https://doi.org/10.1002/ajmg.a.34327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22065612">Aharoni et al. (2011)</a> reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous R315W TRPV4 mutation. Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22065612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8</strong>
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HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607144 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607144;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=rs267607144" 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=rs267607144" 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=RCV000005292 OR RCV000005293 OR RCV000192243 OR RCV000202467 OR RCV000235740 OR RCV000623703 OR RCV000763296 OR RCV003320352" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005292, RCV000005293, RCV000192243, RCV000202467, RCV000235740, RCV000623703, RCV000763296, RCV003320352" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005292...</a>
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<p><strong><em>Distal Hereditary Motor Neuropathy 8, Autosomal Dominant</em></strong></p><p>
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In affected members of a large family in which 20 individuals had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; <a href="/entry/600175">600175</a>), <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> identified a heterozygous c.806G-A transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-his (R269H) substitution. The family had originally been reported by <a href="#16" class="mim-tip-reference" title="Fleury, P., Hageman, G. <strong>A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis.</strong> J. Neurol. Neurosurg. Psychiat. 48: 1037-1048, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4056805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4056805</a>] [<a href="https://doi.org/10.1136/jnnp.48.10.1037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4056805">Fleury and Hageman (1985)</a>. The mutation was not found in 162 European control individuals. The mutation occurred at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4056805+20037588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
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In affected members of the family with hereditary motor and sensory neuropathy type IIC (HMSN2C; <a href="/entry/606071">606071</a>) reported by <a href="#14" class="mim-tip-reference" title="Dyck, P. J., Litchy, W. J., Minnerath, S., Bird, T. D., Chance, P. F., Schaid, D. J., Aronson, A. E. <strong>Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis.</strong> Ann. Neurol. 35: 608-615, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8179305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8179305</a>] [<a href="https://doi.org/10.1002/ana.410350515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8179305">Dyck et al. (1994)</a>, <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> and <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> independently identified a heterozygous R269H mutation in the TRPV4 gene. <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> did not find the mutation in over 700 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> postulated a gain-of-function mechanism. The studies of <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269C; <a href="#0011">605427.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20037587+20037586+8179305" 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>Variant Function</em></strong></p><p>
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Commenting on the divergent functional findings of <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> and <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> and <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a>, <a href="#31" class="mim-tip-reference" title="Nilius, B., Owsianik, G. <strong>Channelopathies converge on TRPV4.</strong> Nature Genet. 42: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20104247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20104247</a>] [<a href="https://doi.org/10.1038/ng0210-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20104247">Nilius and Owsianik (2010)</a> suggested that the discrepancies were related to differences in experimental protocols. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20104247+20037587+20037588+20037586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro functional expression studies, <a href="#20" class="mim-tip-reference" title="Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J. <strong>TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.</strong> Neurology 76: 887-894, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21288981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21288981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21288981[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/10.1212/WNL.0b013e31820f2de3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21288981">Klein et al. (2011)</a> showed that the mutant R269H protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations in HEK293 cells compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The findings were consistent with a pathogenic gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21288981" 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>.0010 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607145 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607145;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=rs267607145" 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=rs267607145" 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=RCV000005294 OR RCV000005295 OR RCV000192245 OR RCV000202561 OR RCV000236285 OR RCV000789587 OR RCV001796956 OR RCV002371763" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005294, RCV000005295, RCV000192245, RCV000202561, RCV000236285, RCV000789587, RCV001796956, RCV002371763" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005294...</a>
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<p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
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In 3 affected members of a family with hereditary motor and sensory neuropathy type IIC (HMSN2C; <a href="/entry/606071">606071</a>), <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> identified a heterozygous c.946C-T transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-cys (R316C) substitution. The mean age at onset was 3 years, with distal lower limb muscle weakness and wasting, areflexia, and vocal cord paralysis. The R316C mutation was also found in 3 affected individuals in another family: 1 had a phenotype of HMSN2C and 2 others had a phenotype consistent with scapuloperoneal spinal muscular atrophy (<a href="/entry/181405">181405</a>). The mean age at onset was 29.2 years, with distal upper and lower limb muscle weakness, atrophy, and areflexia. One patient had scoliosis, 1 had proximal muscle involvement, 1 had sensory symptoms, and 1 had vocal cord paresis. The mutation was not found in 304 European control individuals. The mutation occurs at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20037588" 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>Scapuloperoneal Spinal Muscular Atrophy</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> identified a heterozygous R316C mutation in affected members of a large family with autosomal dominant scapuloperoneal spinal muscular atrophy reported by <a href="#11" class="mim-tip-reference" title="DeLong, R., Siddique, T. <strong>A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features.</strong> Arch. Neurol. 49: 905-908, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1520078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1520078</a>] [<a href="https://doi.org/10.1001/archneur.1992.00530330027010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1520078">DeLong and Siddique (1992)</a>. The mutation was not found in 600 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> postulated a gain-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1520078+20037587" 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>Variant Function</em></strong></p><p>
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Commenting on the divergent functional findings of <a href="#5" class="mim-tip-reference" title="Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. <strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong> Nature Genet. 42: 160-164, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037588[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/ng.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037588">Auer-Grumbach et al. (2010)</a> and <a href="#12" class="mim-tip-reference" title="Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. <strong>Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.</strong> Nature Genet. 42: 165-169, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037587[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/ng.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037587">Deng et al. (2010)</a> and <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a>, <a href="#31" class="mim-tip-reference" title="Nilius, B., Owsianik, G. <strong>Channelopathies converge on TRPV4.</strong> Nature Genet. 42: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20104247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20104247</a>] [<a href="https://doi.org/10.1038/ng0210-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20104247">Nilius and Owsianik (2010)</a> suggested that the discrepancies were related to differences in experimental protocols. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20104247+20037587+20037588+20037586" 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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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8, INCLUDED<br />
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267607146 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607146;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267607146?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607146" 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=rs267607146" 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=RCV000005296 OR RCV000033215 OR RCV000190885 OR RCV000202537 OR RCV000517563 OR RCV000856933 OR RCV001027476 OR RCV002415400" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005296, RCV000033215, RCV000190885, RCV000202537, RCV000517563, RCV000856933, RCV001027476, RCV002415400" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005296...</a>
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<p>In affected members of a family with hereditary motor and sensory neuropathy IIC (HMSN2C; <a href="/entry/606071">606071</a>), <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a> identified a heterozygous c.805C-T transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-cys (R269C) substitution. In vitro functional expression studies showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269H; <a href="#0009">605427.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20037586" 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>Scapuloperoneal Spinal Muscular Atrophy and Autosomal Dominant Distal Hereditary Motor Neuropathy 8</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Berciano, J., Baets, J., Gallardo, E., Zimon, M., Garcia, A., Lopez-Laso, E., Combarros, O., Infante, J., Timmerman, V., Jordanova, A., De Jonghe, P. <strong>Reduced penetrance in hereditary motor neuropathy caused by TRPV4 arg269-to-cys mutation.</strong> J. Neurol. 258: 1413-1421, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21336783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21336783</a>] [<a href="https://doi.org/10.1007/s00415-011-5947-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21336783">Berciano et al. (2011)</a> reported a family in which 2 of 5 individuals carrying the same heterozygous R269C mutation had different phenotypes: a 44-year-old woman had scapuloperoneal spinal muscular atrophy (SPSMA; <a href="/entry/181405">181405</a>) and her 7-year-old daughter had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; <a href="/entry/600175">600175</a>). The 3 other individuals with the mutation were clinically and electrophysiologically asymptomatic 9, 40, and 70 years of age, respectively, consistent with incomplete penetrance. The mother had sloped shoulders since childhood and later developed progressive lower leg muscle weakness and atrophy. She also had transient dysphonia. Muscle biopsy showed evidence of chronic denervation and renervation, and electrophysiologic studies showed reduced compound muscle action potentials with normal nerve conduction velocities, consistent with a motor axonal neuropathy. The daughter was born with congenital arthrogryposis and showed delayed motor development and laryngomalacia with stridor and vocal cord paresis necessitating intermittent tracheostomy placement. She was wheelchair-bound at age 7 due to limited joint mobility and lower limb muscle weakness, and also had weakness and atrophy of the shoulder girdle muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21336783" 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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TRPV4, PRO19SER (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3742030;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3742030</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs3742030 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3742030;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs3742030?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs3742030" 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=rs3742030" 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=RCV000005297 OR RCV000125613 OR RCV000259885 OR RCV000277523 OR RCV000317460 OR RCV000357119 OR RCV000388208 OR RCV000713884 OR RCV001079400 OR RCV001172934 OR RCV002276532" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005297, RCV000125613, RCV000259885, RCV000277523, RCV000317460, RCV000357119, RCV000388208, RCV000713884, RCV001079400, RCV001172934, RCV002276532" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005297...</a>
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<p>In 2 cohorts of elderly individuals, <a href="#39" class="mim-tip-reference" title="Tian, W., Fu, Y., Garcia-Elias, A., Fernandez-Fernandez, J. M., Vicente, R., Kramer, P. L., Klein, R. F., Hitzemann, R., Orwoll, E. S., Wilmot, B., McWeeney, S., Valverde, M. A., Cohen, D. M. <strong>A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.</strong> Proc. Nat. Acad. Sci. 106: 14034-14039, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19666518[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0904084106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19666518">Tian et al. (2009)</a> found that a pro19-to-ser (P19S) polymorphism in the TRPV4 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3742030;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3742030</a>) was significantly associated with serum sodium concentration (<a href="/entry/613508">613508</a>) and with hyponatremia, defined as serum sodium less than 135 mEq/L, in non-Hispanic Caucasian males. Mean serum sodium concentration was lower among subjects with the 19S allele relative to the wildtype 19P allele, and subjects with the minor allele were 2.4 to 6.4 times as likely to exhibit hyponatremia as subjects without the minor allele. Heterologous expression studies in HEK293 cells showed that P19S mutant channels showed diminished response to hypotonic stress and to the osmotransducing lipid epoxyeicosatrienoic acid compared to wildtype channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19666518" 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">rs267607147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607147;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=rs267607147" 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=rs267607147" 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=RCV000005298" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005298" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005298</a>
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<p>In a patient with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for a c.2395C-G transversion in exon 15 of the TRPV4 gene, resulting in a pro799-to-ala (P799A) substitution at an evolutionarily conserved residue in the cytoplasmic domain. <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> noted that pro799 appeared to be a 'hot codon' for MTD mutations (see <a href="#0007">605427.0007</a>, <a href="#0014">605427.0014</a>, and <a href="#0015">605427.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" 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">rs267607147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607147;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=rs267607147" 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=rs267607147" 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=RCV000005299 OR RCV000202484" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005299, RCV000202484" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005299...</a>
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<p>In a patient with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for a c.2395C-T transition in exon 15 of the TRPV4 gene, resulting in a pro799-to-ser (P799S) substitution at an evolutionarily conserved residue in the cytoplasmic domain. <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> noted that pro799 appeared to be a 'hot codon' for MTD mutations (see <a href="#0007">605427.0007</a>, <a href="#0013">605427.0013</a>, and <a href="#0015">605427.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female infant (patient 8) who died at age 4.5 months with MTD, <a href="#3" class="mim-tip-reference" title="Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. <strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong> Orphanet J. Rare Dis. 6: 37, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21658220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21658220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21658220[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/10.1186/1750-1172-6-37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21658220">Andreucci et al. (2011)</a> identified heterozygosity for the P799S variant in the TRPV4 gene. The patient was hospitalized immediately after birth due to skeletal malformations and respiratory difficulties. She had severe cervical instability, and her death was believed to be caused by medullary compression and respiratory decompensation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21658220" 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">rs121912637 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912637;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=rs121912637" 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=rs121912637" 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=RCV000005300 OR RCV000202509 OR RCV005089285" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005300, RCV000202509, RCV005089285" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005300...</a>
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<p>In a patient with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for a c.2396C-G transversion in exon 15 of the TRPV4 gene, resulting in a pro799-to-arg (P799R) substitution at an evolutionarily conserved residue in the cytoplasmic domain. <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> noted that pro799 appeared to be a 'hot codon' for MTD mutations (see <a href="#0007">605427.0007</a>, <a href="#0013">605427.0013</a>, and <a href="#0014">605427.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" 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">rs515726154 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726154;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=rs515726154" 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=rs515726154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for a 3-bp deletion (c.1411delTTC) in exon 8 of the TRPV4 gene, resulting in deletion of phe471 (F471del) from the S1 domain. The authors stated that this was the first reported mutation other than a missense mutation in the TRPV4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with lethal infantile metatropic dysplasia, <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> identified heterozygosity for the F471del mutation, which they described as affecting nucleotides 1412 to 1414. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" 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">rs267607148 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607148;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=rs267607148" 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=rs267607148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; <a href="/entry/184252">184252</a>), <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for an c.832G-A transition in exon 5 of the TRPV4 gene, resulting in a glu278-to-lys (E278K) substitution at an evolutionarily conserved residue in the ANK3 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" 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">rs267607149 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607149;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=rs267607149" 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=rs267607149" 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=RCV000005303 OR RCV000005304 OR RCV000023424 OR RCV000202566 OR RCV001331193 OR RCV001549550 OR RCV001823100 OR RCV001851964" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005303, RCV000005304, RCV000023424, RCV000202566, RCV001331193, RCV001549550, RCV001823100, RCV001851964" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005303...</a>
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<p><strong><em>Spondylometaphyseal Dysplasia, Kozlowski Type</em></strong></p><p>
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In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; <a href="/entry/184252">184252</a>), <a href="#10" class="mim-tip-reference" title="Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. <strong>Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.</strong> J. Med. Genet. 47: 704-709, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577006</a>] [<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577006">Dai et al. (2010)</a> identified heterozygosity for a c.2389G-A transition in exon 15 of the TRPV4 gene, resulting in a glu797-to-lys (E797K) substitution at an evolutionarily conserved residue in the cytoplasmic domain. The authors noted that this was the first SMDK patient to be reported with a mutation in exon 15, which otherwise appears to be a hotspot for mutations causing metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577006" 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>Spondylometaphyseal Dysplasia, Maroteaux Type</em></strong></p><p>
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In an adult woman with the Maroteaux type of spondyloepiphyseal dysplasia (<a href="/entry/184095">184095</a>), <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygosity for the E797K mutation in the TRPV4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503319" 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>Metatropic Dysplasia</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> identified a heterozygous E797K mutation in a patient with a mild form of metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), with little or no scoliosis, mild platyspondyly, mild metaphyseal widening, and carpal ossification delay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" 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">rs515726166 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726166;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=rs515726166" 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=rs515726166" 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=RCV000202488 OR RCV002279935" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202488, RCV002279935" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202488...</a>
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<p>In a Japanese woman with the Maroteaux type of spondyloepiphyseal dysplasia (<a href="/entry/184095">184095</a>), previously reported by <a href="#33" class="mim-tip-reference" title="Nishimura, G., Kizu, R., Kijima, Y., Sakai, K., Kawaguchi, Y., Kimura, T., Matsushita, I., Shirahama, S., Ikeda, T., Ikegawa, S., Hasegawa, T. <strong>Spondyloepiphyseal dysplasia Maroteaux type: report of three patients from two families and exclusion of type II collagen defects.</strong> Am. J. Med. Genet. 120A: 498-502, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12884428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12884428</a>] [<a href="https://doi.org/10.1002/ajmg.a.20095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12884428">Nishimura et al. (2003)</a>, <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygosity for a 17-bp deletion (c.2396del17) in the TRPV4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20503319+12884428" 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">rs387906324 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906324;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=rs387906324" 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=rs387906324" 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=RCV000005306 OR RCV000202438 OR RCV001851965" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005306, RCV000202438, RCV001851965" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005306...</a>
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<p>In a Japanese man with the Maroteaux type of spondyloepiphyseal dysplasia (<a href="/entry/184095">184095</a>), previously reported by <a href="#33" class="mim-tip-reference" title="Nishimura, G., Kizu, R., Kijima, Y., Sakai, K., Kawaguchi, Y., Kimura, T., Matsushita, I., Shirahama, S., Ikeda, T., Ikegawa, S., Hasegawa, T. <strong>Spondyloepiphyseal dysplasia Maroteaux type: report of three patients from two families and exclusion of type II collagen defects.</strong> Am. J. Med. Genet. 120A: 498-502, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12884428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12884428</a>] [<a href="https://doi.org/10.1002/ajmg.a.20095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12884428">Nishimura et al. (2003)</a>, <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygosity for a c.647G-A transition in exon 3 of the TRPV4 gene, resulting in a glu183-to-lys (E183K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20503319+12884428" 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>.0021 SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607150 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607150;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=rs267607150" 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=rs267607150" 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=RCV000023425 OR RCV000202448" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023425, RCV000202448" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023425...</a>
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<p>In a 6.5-year-old boy from a 4-generation family with the Maroteaux type of spondyloepiphyseal dysplasia (<a href="/entry/184095">184095</a>), <a href="#32" class="mim-tip-reference" title="Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.-J., Bedeschi, F., Benedicenti, F., Mendoza-Londono, R., Silengo, M., Schmidt-Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti-Furga, A. <strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong> Am. J. Med. Genet. 152A: 1443-1449, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>] [<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503319">Nishimura et al. (2010)</a> identified heterozygosity for a c.1805A-G transition in exon 11 of the TRPV4 gene, resulting in a tyr602-to-cys (Y602C) substitution. His mother, maternal grandfather, and great-grandmother were also affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503319" 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>.0022 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
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TRPV4, SER542TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906902 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906902;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906902?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906902" 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=rs387906902" 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=RCV000023426 OR RCV000202508" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023426, RCV000202508" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023426...</a>
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<p>In affected members of a large family with hereditary motor and sensory neuropathy type IIC (HMSN2C; <a href="/entry/606071">606071</a>), <a href="#9" class="mim-tip-reference" title="Chen, D.-H., Sul, Y., Weiss, M., Hillel, A., Lipe, H., Wolff, J., Matsushita, M., Raskind, W., Bird, T. <strong>CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene.</strong> Neurology 75: 1968-1975, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21115951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21115951</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21115951[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/10.1212/WNL.0b013e3181ffe4bb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21115951">Chen et al. (2010)</a> identified a heterozygous c.1625C-A transversion in exon 10 of the TRPV4 gene, resulting in a ser542-to-tyr (S542Y) substitution in the transmembrane domain. The mutation was not found in 400 control chromosomes. The distal sensory loss and muscle weakness in this family was relatively mild, and all but 1 patient had vocal cord paresis. In addition, affected individuals had proportional short stature, which was more pronounced in females, and 1 had dolichocephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21115951" 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>.0023 METATROPIC DYSPLASIA</strong>
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TRPV4, THR89ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514473 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514473;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=rs397514473" 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=rs397514473" 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=RCV000023427 OR RCV000202521 OR RCV004549386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023427, RCV000202521, RCV004549386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023427...</a>
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<p>In a patient with lethal neonatal metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> identified heterozygosity for a c.366C-T transition in exon 2 of the TRPV4 gene, resulting in a thr89-to-ile (T89I) substitution in the N-terminal cytoplasmic domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" 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>.0024 METATROPIC DYSPLASIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906903 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906903;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=rs387906903" 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=rs387906903" 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=RCV000023428 OR RCV000202524 OR RCV001315769" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023428, RCV000202524, RCV001315769" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023428...</a>
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<p>In a patient with lethal infantile metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> identified heterozygosity for a c.590A-G transition in exon 4 of the TRPV4 gene, resulting in a lys197-to-arg (K197R) substitution in the ANK2 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" 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="0025" class="mim-anchor"></a>
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<strong>.0025 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8, INCLUDED
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TRPV4, ARG232CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906904 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906904;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=rs387906904" 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=rs387906904" 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=RCV000023429 OR RCV000190886 OR RCV000202445 OR RCV000236017 OR RCV000789594 OR RCV001172888 OR RCV001542600" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023429, RCV000190886, RCV000202445, RCV000236017, RCV000789594, RCV001172888, RCV001542600" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023429...</a>
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<p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
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In a family with hereditary motor and sensory neuropathy type IIC (HMSN2C; <a href="/entry/606071">606071</a>) originally reported by <a href="#13" class="mim-tip-reference" title="Donaghy, M., Kennett, R. <strong>Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy.</strong> J. Neurol. 246: 552-555, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10463355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10463355</a>] [<a href="https://doi.org/10.1007/s004150050402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10463355">Donaghy and Kennett (1999)</a>, <a href="#20" class="mim-tip-reference" title="Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J. <strong>TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.</strong> Neurology 76: 887-894, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21288981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21288981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21288981[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/10.1212/WNL.0b013e31820f2de3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21288981">Klein et al. (2011)</a> identified a heterozygous c.694C-T transition in exon 4 of the TRPV4 gene, resulting in an arg232-to-cys (R232C) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21288981+10463355" 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>Distal Hereditary Motor Neuronopathy 8, Autosomal Dominant</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Astrea, G., Brisca, G., Fiorillo, C., Valle, M., Tosetti, M., Bruno, C., Santorelli, F. M., Battini, R. <strong>Muscle MRI in TRPV4-related congenital distal SMA.</strong> Neurology 78: 364-365, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22291064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22291064</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318245295a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22291064">Astrea et al. (2012)</a> identified an R232C mutation in an 11-year-old girl with autosomal dominant distal hereditary motor neuropathy-8 (HMND8; <a href="/entry/600175">600175</a>). She had proximal and distal muscle weakness, atrophy of the distal leg muscles, and clubfoot. MRI of the thighs and calf muscles showed extensive fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves. This pattern was distinct when compared to a patient with non-TRPV4 spinal muscular atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22291064" 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>.0026 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906905;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=rs387906905" 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=rs387906905" 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=RCV000023430 OR RCV000202476 OR RCV000415397 OR RCV000497541 OR RCV000856932" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023430, RCV000202476, RCV000415397, RCV000497541, RCV000856932" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023430...</a>
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<p>In a 30-year-old man with HMSN2C (<a href="/entry/606071">606071</a>), <a href="#20" class="mim-tip-reference" title="Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J. <strong>TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.</strong> Neurology 76: 887-894, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21288981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21288981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21288981[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/10.1212/WNL.0b013e31820f2de3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21288981">Klein et al. (2011)</a> identified a de novo heterozygous c.947G-A transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-his (R316H) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21288981" 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>.0027 METATROPIC DYSPLASIA</strong>
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TRPV4, GLY78TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514474 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514474;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=rs397514474" 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=rs397514474" 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=RCV000023431 OR RCV000202458" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023431, RCV000202458" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023431...</a>
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<p>In a 21-week-old fetus with severe metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>) and fetal akinesia, <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a gly78-to-trp (G78W) substitution in a conserved residue. Prenatal ultrasound at age 20 weeks' gestation showed short long bones, narrow bell-shaped thorax, finger contractures, and undetectable fetal movements. After termination, the fetus was found to have short long bones with mildly accentuated metaphyses, cartilaginous expansions of the elbow, wrist, and knee joints, relatively long hands and feet, and flattened vertebral bodies. <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in this patient, and suggested that this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964829" 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>.0028 METATROPIC DYSPLASIA</strong>
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TRPV4, THR740ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906906 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906906;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=rs387906906" 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=rs387906906" 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=RCV000023432 OR RCV000202544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023432, RCV000202544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023432...</a>
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<p>In a pair of 20-week-old monozygotic twins with severe metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>) and fetal akinesia, <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a thr740-to-ile (T740I) substitution in a conserved residue. Absence of fetal movements with arthrogryposis was detected on prenatal ultrasound. Both fetuses had short long bones, thoracic hypoplasia, a sacrococcygeal tail, and contractures. <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and suggested that this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964829" 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>.0029 METATROPIC DYSPLASIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906907 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906907;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=rs387906907" 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=rs387906907" 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=RCV000023433 OR RCV000202517 OR RCV000413499" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023433, RCV000202517, RCV000413499" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023433...</a>
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<p>In a male infant, born of consanguineous Algerian parents, with severe metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a lys276-to-glu (K276E) substitution in a conserved residue. The mother noted diminished fetal movements during pregnancy, which was confirmed by ultrasound. At birth the infant was noted to have severe contractures consistent with fetal akinesia syndrome, thoracic hypoplasia, clubfeet, camptodactyly, and enlarged joints. Radiographs confirmed metatropic dysplasia. The legs could not be straightened and remained in a flexed and adducted position. Although neonatal neurologic examination was normal, except for restricted movements, electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. <a href="#40" class="mim-tip-reference" title="Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A. <strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong> Am. J. Med. Genet. 155A: 2860-2864, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>] [<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964829">Unger et al. (2011)</a> noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in this patient, and since electrophysiologic studies indicated a neuropathic process, this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964829" 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>.0030 DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs515726170 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726170;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=rs515726170" 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=rs515726170" 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=RCV000202455" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202455" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202455</a>
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<p>In all affected members of a family with digital arthropathy-brachydactyly (FDAB; <a href="/entry/606835">606835</a>), originally reported by <a href="#2" class="mim-tip-reference" title="Amor, D. J., Tudball, C., Gardner, R. J. M., Lamande, S. R., Bateman, J. F., Savarirayan, R. <strong>Familial digital arthropathy-brachydactyly.</strong> Am. J. Med. Genet. 108: 235-240, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11891693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11891693</a>] [<a href="https://doi.org/10.1002/ajmg.10269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11891693">Amor et al. (2002)</a>, <a href="#22" class="mim-tip-reference" title="Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F. <strong>Mutations in TRPV4 cause an inherited arthropathy of hands and feet.</strong> Nature Genet. 43: 1142-1146, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964574</a>] [<a href="https://doi.org/10.1038/ng.945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964574">Lamande et al. (2011)</a> identified heterozygosity for an c.819C-G transversion in exon 5 of the TRPV4 gene, resulting in a phe273-to-leu (F273L) substitution at a highly conserved residue within finger loop 3. The mutation was not found in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11891693+21964574" 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>.0031 DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907219;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387907219?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387907219" 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=rs387907219" 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=RCV000029173" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029173" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029173</a>
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<p>In all 5 affected members of a family with digital arthropathy-brachydactyly (FDAB; <a href="/entry/606835">606835</a>), <a href="#22" class="mim-tip-reference" title="Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F. <strong>Mutations in TRPV4 cause an inherited arthropathy of hands and feet.</strong> Nature Genet. 43: 1142-1146, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964574</a>] [<a href="https://doi.org/10.1038/ng.945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964574">Lamande et al. (2011)</a> identified heterozygosity for an c.812G-C transversion in exon 5 of the TRPV4 gene, resulting in an arg271-to-pro (R271P) substitution at a highly conserved residue within finger loop 3. The mutation was not found in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964574" 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>.0032 DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL</strong>
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TRPV4, GLY270VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907220 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907220;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=rs387907220" 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=rs387907220" 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=RCV000029174" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029174" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029174</a>
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<p>In a man with digital arthropathy-brachydactyly (FDAB; <a href="/entry/606835">606835</a>), <a href="#22" class="mim-tip-reference" title="Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F. <strong>Mutations in TRPV4 cause an inherited arthropathy of hands and feet.</strong> Nature Genet. 43: 1142-1146, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964574</a>] [<a href="https://doi.org/10.1038/ng.945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964574">Lamande et al. (2011)</a> identified heterozygosity for an c.809G-T transversion in exon 5 of the TRPV4 gene, resulting in a gly270-to-val (G270V) substitution at a highly conserved residue within finger loop 3. The mutation was not found in the patient's unaffected sister or in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964574" 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>.0033 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514494;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=rs397514494" 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=rs397514494" 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=RCV000032600 OR RCV000190887 OR RCV000202485 OR RCV000235384 OR RCV001265863" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032600, RCV000190887, RCV000202485, RCV000235384, RCV001265863" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032600...</a>
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<p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
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In 3 members of a family with HMSN2C (<a href="/entry/606071">606071</a>), <a href="#24" class="mim-tip-reference" title="Landoure, G., Sullivan, J. M., Johnson, J. O., Munns, C. H., Shi, Y., Diallo, O., Gibbs, J. R., Gaudet, R., Ludlow, C. L., Fischbeck, K. H., Traynor, B. J., Burnett, B. G., Sumner, C. J. <strong>Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family.</strong> Neurology 79: 192-194, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22675077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22675077</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31825f04b2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22675077">Landoure et al. (2012)</a> identified a heterozygous c.557G-A transition in the TRPV4 gene, resulting in an arg186-to-gln (R186Q) substitution at a highly conserved residue situated on the convex face of the ankyrin repeat domain (ARD). The mutation was found by exome sequencing and confirmed by Sanger sequencing. This family had previously been reported as family 3 in <a href="#25" class="mim-tip-reference" title="Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. <strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong> Nature Genet. 42: 170-174, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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/ng.512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20037586">Landoure et al. (2010)</a>, but the primers used in that study did not identify the TRPV4 mutation. Functional expression studies in HEK293 cells showed that the R186Q mutant protein resulted in increased calcium levels and increased cell death, suggesting abnormal constitutive TRPV4 activity, as observed with the R269C (<a href="#0011">605427.0011</a>) mutant. The patients had progressive distal limb muscle weakness and atrophy, hoarse voice, and stridor on exertion. Nerve conduction studies confirmed an axonal neuropathy with phrenic nerve involvement. Two patients had scoliosis and 1 had sensorineural hearing loss, but none had skeletal dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22675077+20037586" 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>Distal Hereditary Motor Neuronopathy Type VIII</em></strong></p><p>
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<a href="#15" class="mim-tip-reference" title="Echaniz-Laguna, A., Dubourg, O., Carlier, P., Carlier, R.-Y., Sabouraud, P., Pereon, Y., Chapon, F., Thauvin-Robinet, C., Laforet, P., Eymard, B., Latour, P., Stojkovic, T. <strong>Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy.</strong> Neurology 82: 1919-1926, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24789864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24789864</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24789864">Echaniz-Laguna et al. (2014)</a> identified a heterozygous R186Q mutation in a child with autosomal dominant distal hereditary motor neuropathy-8 (HMND8; <a href="/entry/600175">600175</a>). The patient's unaffected mother also carried the mutation, consistent with incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24789864" 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">rs1057520305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057520305;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=rs1057520305" 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=rs1057520305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 sibs from a Greek family with avascular necrosis of the femoral head (ANFH2; <a href="/entry/617383">617383</a>), <a href="#28" class="mim-tip-reference" title="Mah, W., Sonkusare, S. K., Wang, T., Azeddine, B., Pupavac, M., Carrot-Zhang, J., Hong, K., Majewski, J., Harvey, E. J., Russell, L., Chalk, C., Rosenblatt, D. S., Nelson, M. T., Seguin, C. <strong>Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.</strong> J. Med. Genet. 53: 705-709, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27330106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27330106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27330106[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/10.1136/jmedgenet-2016-103829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27330106">Mah et al. (2016)</a> identified heterozygosity for a 4-bp deletion (c.2480_2483delCCCG, NM_021625.4) followed by a c.2486T-A transversion (c.2486T-A, NM_021625.4) in a highly conserved region of the TRPV4 gene, causing a frameshift that results in a premature termination codon (Val829TrpfsTer3). The mutation was not found in an unaffected brother, or in the 1000 Genomes or Exome Variant Server databases; parental DNA was unavailable, but the sibs' father reportedly had symptoms of joint pain that were never evaluated. Functional analysis in patient fibroblasts and transduced HEK293 cells indicated that the mutation results in a gain-of-function of TRPV4 channels by impeding channel closure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27330106" 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">rs515726163 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726163;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=rs515726163" 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=rs515726163" 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=RCV000202495 OR RCV000497423 OR RCV000755170" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202495, RCV000497423, RCV000755170" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202495...</a>
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<p>In a patient (R09-035) with a neonatal lethal form of metatropic dysplasia (MTD; <a href="/entry/156530">156530</a>), <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> identified heterozygosity for an c.1853T-C transition in exon 12 of the TRPV4 gene that resulted in a leu618-to-pro (L618P) substitution at a highly evolutionarily conserved amino acid residue in transmembrane segment 5 (TM5). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient (R09-440A) with nonlethal MTD, <a href="#42" class="mim-tip-reference" title="Weinstein, M. M., Kang, T., Lachman, R. S., Bamshad, M., Nickerson, D. A., Krakow, D., Cohn, D. H. <strong>Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 170A: 3298-3302, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27530454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27530454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27530454[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/10.1002/ajmg.a.37942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27530454">Weinstein et al. (2016)</a> detected somatic mosaicism for the L618P mutation in TRPV4 previously identified by <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a>. Sanger sequencing was negative for mutations in all of the coding exons of TRPV4, as well as of other genes consistent with the phenotype. Subsequent exome sequencing detected a c.1853T-C transition in 16 of 71 reads, consistent with somatic mosaicism. Parental exomes were negative for the mutation. Comparison of the levels of the mutant allele in this patient with those of the patient of <a href="#8" class="mim-tip-reference" title="Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. <strong>Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 152A: 1169-1177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425821</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425821[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/10.1002/ajmg.a.33392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20425821">Camacho et al. (2010)</a> showed that 15% of alleles in blood cells contained the mutation, implying that about 30% of cells in the patient would be expected to be heterozygous for the L618P allele. However, the level of mosaicism in the target tissue (cartilage) could not be assessed directly because a sample was not available. <a href="#42" class="mim-tip-reference" title="Weinstein, M. M., Kang, T., Lachman, R. S., Bamshad, M., Nickerson, D. A., Krakow, D., Cohn, D. H. <strong>Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.</strong> Am. J. Med. Genet. 170A: 3298-3302, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27530454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27530454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27530454[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/10.1002/ajmg.a.37942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27530454">Weinstein et al. (2016)</a> noted that high-throughput sequencing can have higher sensitivity for the detection of mosaicism than Sanger sequence analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27530454+20425821" 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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Aharoni, S., Harlalka, G., Offiah, A., Shuper, A., Crosby, A. H., McEntagart, M.
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<strong>Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorder.</strong>
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Am. J. Med. Genet. 155A: 3153-3156, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22065612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22065612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22065612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.34327" target="_blank">Full Text</a>]
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Amor, D. J., Tudball, C., Gardner, R. J. M., Lamande, S. R., Bateman, J. F., Savarirayan, R.
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<strong>Familial digital arthropathy-brachydactyly.</strong>
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Am. J. Med. Genet. 108: 235-240, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11891693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11891693</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11891693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.10269" target="_blank">Full Text</a>]
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Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R.
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<strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong>
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Orphanet J. Rare Dis. 6: 37, 2011.
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[<a href="https://doi.org/10.1186/1750-1172-6-37" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e318245295a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00443368" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00415-011-5947-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33392" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181ffe4bb" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.075358" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1992.00530330027010" target="_blank">Full Text</a>]
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<strong>Metatropic dysplasia: clinical and radiologic findings in 11 patients demonstrating long-term natural history.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.31941" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J.
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<strong>TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21288981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21288981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21288981[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=21288981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31820f2de3" target="_blank">Full Text</a>]
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<div class="">
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Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H.
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<strong>Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.</strong>
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Am. J. Hum. Genet. 84: 307-315, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19232556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19232556[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=19232556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2009.01.021" target="_blank">Full Text</a>]
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<a id="Lamande2011" class="mim-anchor"></a>
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<div class="">
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Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F.
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<strong>Mutations in TRPV4 cause an inherited arthropathy of hands and feet.</strong>
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Nature Genet. 43: 1142-1146, 2011.
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[<a href="https://doi.org/10.1038/ng.945" target="_blank">Full Text</a>]
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<div class="">
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Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E.
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<strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations.</strong>
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Hum. Molec. Genet. 21: 2166-2180, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22328087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22328087</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22328087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/dds032" target="_blank">Full Text</a>]
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<div class="">
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Landoure, G., Sullivan, J. M., Johnson, J. O., Munns, C. H., Shi, Y., Diallo, O., Gibbs, J. R., Gaudet, R., Ludlow, C. L., Fischbeck, K. H., Traynor, B. J., Burnett, B. G., Sumner, C. J.
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<strong>Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22675077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22675077</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22675077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31825f04b2" target="_blank">Full Text</a>]
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Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others.
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<strong>Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20037586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20037586[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=20037586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.512" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)00143-4" target="_blank">Full Text</a>]
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<strong>TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18719094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18719094</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18719094[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=18719094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0803970105" target="_blank">Full Text</a>]
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Mah, W., Sonkusare, S. K., Wang, T., Azeddine, B., Pupavac, M., Carrot-Zhang, J., Hong, K., Majewski, J., Harvey, E. J., Russell, L., Chalk, C., Rosenblatt, D. S., Nelson, M. T., Seguin, C.
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<strong>Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27330106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27330106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27330106[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=27330106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2016-103829" target="_blank">Full Text</a>]
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<a id="McEntagart2005" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668982</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20375" target="_blank">Full Text</a>]
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<strong>Spondyloepimetaphyseal dysplasia of Maroteaux (pseudo-Morquio type II syndrome): report of a new patient and review of the literature.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14755468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14755468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14755468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20442" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20104247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20104247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20104247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0210-98" target="_blank">Full Text</a>]
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<a id="Nishimura2010" class="mim-anchor"></a>
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<strong>Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503319</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33414" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12884428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12884428</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12884428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20095" target="_blank">Full Text</a>]
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Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H.
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<strong>Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.</strong>
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Nature Genet. 40: 999-1003, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587396[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=18587396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.166" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Sidhaye2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sidhaye, V. K., Guler, A. D., Schweitzer, K. S., D'Alessio, F., Caterina, M. J., King, L. S.
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<strong>Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.</strong>
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Proc. Nat. Acad. Sci. 103: 4747-4752, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537379[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=16537379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0511211103" target="_blank">Full Text</a>]
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<a id="Sonkusare2012" class="mim-anchor"></a>
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Sonkusare, S. K., Bonev, A. D., Ledoux, J., Liedtke, W., Kotlikoff, M. I., Heppner, T. J., Hill-Eubanks, D. C., Nelson, M. T.
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<strong>Elementary Ca(2+) signals through endothelial TRPV4 channels regulate vascular function.</strong>
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Science 336: 597-601, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22556255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22556255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22556255[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=22556255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1216283" target="_blank">Full Text</a>]
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<a id="Strotmann2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., Plant, T. D.
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<strong>OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.</strong>
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Nature Cell. Biol. 2: 695-702, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11025659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11025659</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11025659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/35036318" target="_blank">Full Text</a>]
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<a id="Suzuki2003" class="mim-anchor"></a>
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Suzuki, M., Mizuno, A., Kodaira, K., Imai, M.
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<strong>Impaired pressure sensation in mice lacking TRPV4.</strong>
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J. Biol. Chem. 278: 22664-22668, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12692122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12692122</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12692122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M302561200" target="_blank">Full Text</a>]
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<a id="Tian2009" class="mim-anchor"></a>
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Tian, W., Fu, Y., Garcia-Elias, A., Fernandez-Fernandez, J. M., Vicente, R., Kramer, P. L., Klein, R. F., Hitzemann, R., Orwoll, E. S., Wilmot, B., McWeeney, S., Valverde, M. A., Cohen, D. M.
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<strong>A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.</strong>
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Proc. Nat. Acad. Sci. 106: 14034-14039, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19666518[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=19666518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0904084106" target="_blank">Full Text</a>]
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<a id="Unger2011" class="mim-anchor"></a>
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Unger, S., Lausch, E., Stanzial, F., Gillessen-Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi-Vici, C., Nilius, B., Zabel, B., Superti-Furga, A.
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<strong>Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy?</strong>
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Am. J. Med. Genet. 155A: 2860-2864, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964829</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.34268" target="_blank">Full Text</a>]
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<a id="Watanabe2003" class="mim-anchor"></a>
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Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., Nilius, B.
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<strong>Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.</strong>
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Nature 424: 434-438, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879072</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12879072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature01807" target="_blank">Full Text</a>]
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Weinstein, M. M., Kang, T., Lachman, R. S., Bamshad, M., Nickerson, D. A., Krakow, D., Cohn, D. H.
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<strong>Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.</strong>
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Am. J. Med. Genet. 170A: 3298-3302, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27530454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27530454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27530454[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=27530454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37942" target="_blank">Full Text</a>]
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Wissenbach, U., Bodding, M., Freichel, M., Flockerzi, V.
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<strong>Trp12, a novel Trp related protein from kidney</strong>
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FEBS Lett. 485: 127-134, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11094154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11094154</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11094154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(00)02212-2" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 01/31/2022
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Marla J. F. O'Neill - updated : 09/07/2021<br>Marla J. F. O'Neill - updated : 03/02/2017<br>Cassandra L. Kniffin - updated : 9/8/2015<br>Patricia A. Hartz - updated : 7/8/2013<br>Cassandra L. Kniffin - updated : 10/24/2012<br>Marla J. F. O'Neill - updated : 7/17/2012<br>Ada Hamosh - updated : 5/30/2012<br>Cassandra L. Kniffin - updated : 2/28/2012<br>Cassandra L. Kniffin - updated : 12/22/2011<br>Cassandra L. Kniffin - updated : 10/11/2011<br>Cassandra L. Kniffin - updated : 9/13/2011<br>Cassandra L. Kniffin - updated : 6/28/2011<br>Cassandra L. Kniffin - updated : 2/16/2011<br>Marla J. F. O'Neill - updated : 12/22/2010<br>Marla J. F. O'Neill - updated : 12/1/2010<br>Marla J. F. O'Neill - updated : 7/27/2010<br>Cassandra L. Kniffin - updated : 2/24/2010<br>Patricia A. Hartz - updated : 11/19/2009<br>Ada Hamosh - updated : 5/19/2009<br>Ada Hamosh - updated : 10/24/2008<br>Patricia A. Hartz - updated : 1/17/2008<br>Patricia A. Hartz - updated : 6/5/2006<br>Marla J. F. O'Neill - updated : 2/4/2004<br>Ada Hamosh - updated : 8/5/2003<br>Paul J. Converse - updated : 2/16/2001
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Stylianos E. Antonarakis : 11/28/2000
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alopez : 10/17/2023<br>alopez : 01/31/2022<br>alopez : 09/07/2021<br>carol : 03/03/2017<br>carol : 03/02/2017<br>alopez : 09/16/2015<br>ckniffin : 9/8/2015<br>carol : 3/12/2015<br>mgross : 7/8/2013<br>terry : 11/8/2012<br>carol : 11/5/2012<br>ckniffin : 10/24/2012<br>carol : 7/18/2012<br>terry : 7/17/2012<br>alopez : 6/1/2012<br>terry : 5/30/2012<br>carol : 3/7/2012<br>terry : 3/5/2012<br>ckniffin : 2/28/2012<br>carol : 12/22/2011<br>ckniffin : 12/22/2011<br>carol : 10/14/2011<br>terry : 10/12/2011<br>ckniffin : 10/11/2011<br>carol : 9/19/2011<br>ckniffin : 9/13/2011<br>wwang : 7/13/2011<br>ckniffin : 6/28/2011<br>wwang : 3/8/2011<br>ckniffin : 2/16/2011<br>carol : 12/22/2010<br>carol : 12/17/2010<br>wwang : 12/3/2010<br>terry : 12/1/2010<br>alopez : 7/28/2010<br>alopez : 7/28/2010<br>terry : 7/27/2010<br>alopez : 3/4/2010<br>ckniffin : 2/24/2010<br>mgross : 12/1/2009<br>terry : 11/19/2009<br>terry : 5/29/2009<br>carol : 5/29/2009<br>terry : 5/19/2009<br>alopez : 11/14/2008<br>terry : 10/24/2008<br>mgross : 2/6/2008<br>terry : 1/17/2008<br>mgross : 6/6/2006<br>mgross : 6/6/2006<br>terry : 6/5/2006<br>terry : 4/5/2005<br>carol : 2/4/2004<br>alopez : 8/6/2003<br>terry : 8/5/2003<br>mgross : 1/30/2002<br>mgross : 2/21/2001<br>terry : 2/16/2001<br>mgross : 11/28/2000
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<strong>*</strong> 605427
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TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4
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<h4>
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<span class="mim-font">
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VANILLOID RECEPTOR-RELATED OSMOTICALLY ACTIVATED CHANNEL; VROAC<br />
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OSM9-LIKE TRANSIENT RECEPTOR POTENTIAL CHANNEL 4; OTRPC4<br />
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TRANSIENT RECEPTOR POTENTIAL CHANNEL 12; TRP12<br />
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TRANSIENT RECEPTOR POTENTIAL, DROSOPHILA, HOMOLOG OF, 12
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TRPV4</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 111304003, 22764001, 230248006, 717010007, 717264003, 719204007, 722210007, 763067000;
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<strong>ICD10CM:</strong> G12.1;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 12q24.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:109,783,087-109,833,398 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="11">
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<span class="mim-font">
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12q24.11
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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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?Avascular necrosis of femoral head, primary, 2
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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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617383
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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[Sodium serum level QTL 1]
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</span>
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</td>
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<td>
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<span class="mim-font">
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613508
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Brachyolmia type 3
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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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113500
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Digital arthropathy-brachydactyly, familial
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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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606835
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Hereditary motor and sensory neuropathy, type IIc
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</span>
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</td>
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<td>
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<span class="mim-font">
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606071
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Metatropic dysplasia
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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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156530
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Neuronopathy, distal hereditary motor, autosomal dominant 8
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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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600175
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
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Parastremmatic dwarfism
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
168400
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</span>
|
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</td>
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|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Scapuloperoneal spinal muscular atrophy
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
181405
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
SED, Maroteaux type
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
184095
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spondylometaphyseal dysplasia, Kozlowski type
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
184252
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The TRPV4 cation channel mediates calcium influx in response to physical, chemical, and hormonal stimuli in ciliated epithelial cells (Lorenzo et al., 2008). </p>
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|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, Liedtke et al. (2000) isolated cDNAs encoding the vanilloid receptor (VR1; 602076)-related osmotically activated channel, or VROAC, from rat, mouse, human, and chicken. The predicted 872-amino acid VROAC protein has a structure similar to VR1 and VR-like receptor-1 (VRL1, or TRPV2; 606676), with 6 predicted membrane-spanning domains and a putative pore loop. The N-terminal domain of VROAC bears 3 ankyrin repeats and, like its C terminus, is predicted to occur intracellularly. VROAC is a cation-selective channel that is gated by exposure to hypotonicity within the physiologic range. Northern blot analysis of rat tissues detected abundant expression of a 3.2-kb transcript in kidney, lung, spleen, testis, and fat, with lower expression in sensory ganglia. In situ hybridization showed that in the central nervous system, VROAC is expressed in neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. VROAC was also expressed in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells. </p><p>Strotmann et al. (2000) also cloned VROAC, which they termed OTRPC4 due to its similarity to other members of the Osm9 subfamily of transient receptor potential channels (e.g., VR1). In situ hybridization analysis revealed transcripts in the inner cortex and a punctate distribution in the outer cortex of mouse kidney. </p><p>Wissenbach et al. (2000) also cloned VROAC, which they called TRP12. The human protein is 96% identical to the mouse protein. </p><p>Using immunohistochemical analysis, Lorenzo et al. (2008) detected Trpv4 in mouse ciliated tracheal epithelial cells. </p><p>Lamande et al. (2011) analyzed Trpv4 expression in mice and observed that localization and expression are similar in knee and phalangeal joints. In the growth plate, Trpv4 was most highly expressed in the proliferative zone, whereas it was downregulated as chondrocytes matured in the prehypertrophic zone and was not detectable by immunohistochemistry in hypertrophic chondrocytes. Trpv4 was expressed at comparable levels in proliferative and articular chondrocytes. </p>
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</span>
|
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<div>
|
|
<br />
|
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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<span class="mim-text-font">
|
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<p>Wissenbach et al. (2000) determined that the TRPV4 gene contains 15 exons. </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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
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</span>
|
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</h4>
|
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</div>
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|
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<span class="mim-text-font">
|
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<p>By genomic sequence analysis, Liedtke et al. (2000) mapped the TRPV4 gene to chromosome 12q24.1. They mapped the mouse Trpv4 gene to distal chromosome 5 by radiation hybrid analysis. </p>
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|
</span>
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Wissenbach et al. (2000) found that hypoosmotic conditions rapidly activated TRP12, while hyperosmotic conditions inhibited the activity. </p><p>Strotmann et al. (2000) showed that OTRPC4 was responsive to changes in extracellular osmolarity in the physiologically relevant range and was expressed in tissues exposed to changing osmotic environments. </p><p>Watanabe et al. (2003) demonstrated that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome p450 epoxygenase (601258)-dependent formation of epoxyeicosatrienoic acids. Application of 5-prime,6-prime-epoxyeicosatrienoic acid at submicromolar concentrations activated TRPV4 in a membrane-delimited manner and caused calcium influx through TRPV4-like channels in vascular endothelial cells. Watanabe et al. (2003) concluded that activation of TRPV4 in vascular endothelial cells might contribute to the relaxant effects of endocannabinoids and their p450 epoxygenase-dependent metabolites on vascular tone. </p><p>Sidhaye et al. (2006) observed a dose-responsive decrease in Aqp5 (600442) abundance in mouse lung epithelial cells exposed to hypotonic medium. Hypotonic reduction of Aqp5 was augmented and reduced, respectively, by conditions that activated or inhibited Trpv4. Hypotonic reduction of Aqp5 required extracellular calcium and was associated with increased intracellular calcium. The response to hypotonicity was recapitulated by coexpression of TRPV4 and AQP5 in human embryonic kidney cells. Sidhaye et al. (2006) concluded that AQP5 abundance is tightly controlled along a spectrum of extracellular osmolalities and that its abundance in hypotonic conditions can be regulated by TRPV4 activation. </p><p>Using immunofluorescence analysis, Gevaert et al. (2007) detected Trpv4 expression in mouse and rat urothelium and vascular endothelium, but not in other bladder cell types. By measuring intracellular Ca(2+), they found that mouse urothelial cells displayed a Trpv4-dependent response to phorbol esters and to hypotonic cell swelling. Gevaert et al. (2007) concluded that TRPV4 has a role in bladder function. </p><p>The rate of mucociliary clearance in the airways is a function of ciliary beat frequency. Lorenzo et al. (2008) found that tracheal cells from wildtype mice, but not those from Trpv4 -/- mice, increased intracellular Ca(2+) concentration and ciliary beat frequency in response to chemical activation, mildly increased temperature, and ATP application. Both mutant and wildtype cells increased ciliary beat frequency in response to high viscosity solutions. Lorenzo et al. (2008) concluded that TRPV4 in tracheal epithelial cells transduces physical and chemical stimuli into a Ca(2+) signal that regulates ciliary beat frequency and mucociliary transport. </p><p>Landoure et al. (2010) found low levels of TRPV4 expression in human dorsal and ventral spinal cords, at approximately 95% lower levels compared to tracheal cartilage. </p><p>Sonkusare et al. (2012) identified local calcium ion signals, which they called sparklets, in the vascular endothelium of resistance arteries that represent calcium ion influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a 4-channel cluster was cooperative, with activation of as few as 3 channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small-conductance (SK) calcium ion-sensitive potassium channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. Sonkusare et al. (2012) concluded that their results supported the concept that calcium ion influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high calcium ion sensitivity of IK and SK channels to cause vasodilation. </p><p>Using various methods, Lanciotti et al. (2012) found that MLC1 (605908), TRPV4, HEPACAM (611642), syntrophin (see 601017), caveolin-1 (CAV1; 601047), Kir4.1 (KCNJ10; 602208), and AQP4 (600308) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress. </p>
|
|
</span>
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
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</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Skeletal Disorders</em></strong></p><p>
|
|
Rock et al. (2008) identified missense mutations in the TRPV4 gene in 2 families segregating autosomal dominant brachyolmia (BCYM3; 113500). Expression of the R616Q mutation (605427.0001) in human embryonic kidney cells yielded a much larger constitutive current before agonist application. The shape of the IV curve and the reversal potentials were not changed. Rock et al. (2008) demonstrated significantly increased constitutively activated current in the mutant. Similar data were obtained for the mutation encoding V620I (605427.0002), with a significantly increased constitutive current at +100 mV, albeit somewhat less increased than for the R616Q mutant. Thus, both missense mutations conferred a gain-of-function phenotype by significantly increasing the fraction of constitutively open channels and by potentiating agonist activation. Rock et al. (2008) suggested that the data presented in their paper contributed to evidence that TRPV4 is a key regulatory molecule in the growth plate. </p><p>In 6 patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified heterozygous mutations in the TRPV4 gene. Four of the patients had an R594H mutation (605427.0003) in the cytoplasmic S4 domain, which is associated with increased intracellular calcium ion concentration and activity. </p><p>In 2 patients with metatropic dysplasia (MTD; 156530), Krakow et al. (2009) identified heterozygous missense mutations in the TRPV4 gene: I331F (605427.0006) in the ankyrin-5 domain and a cytoplasmic mutation (P799L; 605427.0007). Both mutations occurred de novo. Because mutations in the TRPV4 gene produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal dominant brachyolmia to Kozlowski-type SMD to autosomal dominant metatropic dysplasia, Krakow et al. (2009) suggested that these disorders should be grouped into a new bone dysplasia family. </p><p>Dai et al. (2010) analyzed the TRPV4 gene in 22 MTD probands and 20 SMDK probands, and identified heterozygous TRPV4 mutations in all, except for 1 MTD proband. In the MTD patients, the recurrent P799L mutation was found in 9 patients, and 4 more patients had 3 different substitutions at the pro799 codon (605427.0013-605427.0015). The remaining 8 MTD patients included 7 with novel missense mutations and 1 with a 3-bp deletion of a codon (F471del; 605427.0016), which the authors stated was the first mutation other than a missense mutation to be reported in the TRPV4 gene. In the SMDK patients, the recurrent R594H mutation was found in 12 patients, and 8 had novel missense mutations (see, e.g., 605427.0017 and 605427.0018). Dai et al. (2010) designated pro799 in exon 15 of the TRPV4 gene as a 'hot codon' for MTD mutations and arg594 in exon 11 as a hotspot for SMDK mutations. Dai et al. (2010) noted that although some radiologic signs are shared by both disorders, the presence or absence of dumbbell-shaped femurs ascertained distinction between MTD and SMDK, respectively. </p><p>In 6 patients with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygous mutations in the TRPV4 gene (see, e.g., 605427.0019-605427.0021), 2 of which had previously been identified in patients with MTD (605427.0007) and SMDK (605427.0018). In a patient with parastremmatic dwarfism (168400), they identified heterozygosity for a missense mutation in TRPV4 (R594H; 605427.0003) that had previously been found in patients with SMDK (184252). Nishimura et al. (2010) noted that genotype/phenotype correlations did not appear to be robust, and suggested that in the presence of a TRPV4 mutation, modulation of the clinical phenotype by other genes and/or by nongenetic factors might occur. </p><p>Camacho et al. (2010) reported 10 patients with varying severity of metatropic dysplasia, all of whom carried a heterozygous mutation in the TRPV4 gene (see, e.g., 605427.0006-605427.0007, 605427.0023-605427.0024). Five patients had a lethal form of the disorder with death in the neonatal period or infancy, whereas 5 had a nonlethal disorder classified as mild, moderately severe, or severe. There was no clear relationship between the severity of the disorder and type of mutation or domain affected, but Camacho et al. (2010) suggested that the degree of constitutive activation of the mutant channels likely correlates with disease severity. Histologic studies of bone derived from 2 lethal cases showed abnormally thick cartilage with nodular proliferation, short diaphyses, and abnormal bone formation, indicating disrupted endochondral ossification. There was also evidence of abnormal chondrogenesis and abnormal differentiation of mesenchymal progenitors as well as lack of normal columns of chondrocytes. Camacho et al. (2010) suggested that the mechanism of disease may result from increased calcium in chondrocytes. </p><p>Unger et al. (2011) reported 4 patients, including a pair of monozygotic twins, with a severe lethal form of metatropic dysplasia associated with fetal akinesia. Three of the 4 were found to have absent movements, severe contractures, and features of metatropic dysplasia on prenatal ultrasound, and the pregnancies were terminated. The fourth patient presented with multiple joint contractures and absent limb movements at birth, consistent with fetal akinesia. Features of severe metatropic dysplasia in these patients included short long bones, cartilaginous joint expansion, narrow thorax, flat vertebral bodies, and sacrococcygeal tail. The fourth patient had a normal neonatal neurologic examination, although movement was restricted, but electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. Genetic analysis of the 4 patients identified 3 different heterozygous de novo missense mutations in the TRPV4 gene (605427.0027-605427.0029). Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and since electrophysiologic studies of 1 indicated a neuropathic process, these TRPV4 mutations may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. </p><p>In a cohort of 26 patients diagnosed with various skeletal dysplasias, including 15 with MTD, 9 with SMDK, and 2 with brachyolmia, Andreucci et al. (2011) sequenced the TRPV4 gene and identified heterozygosity for missense mutations in 21 of them, including 14 patients with a diagnosis of MTD and 7 patients with SMDK (see, e.g., 605427.0003, 605427.0007, 605427.0014). In addition, 1 patient (case 17) with SMDK was heterozygous for a 3-bp duplication (L523dup). The 4 patients in whom no mutation was detected in the TRPV4 gene all exhibited atypical features for their respective clinical diagnoses. </p><p>In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, Grigelioniene et al. (2014) identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene (605427.0001), which segregated fully with disease. </p><p>In 4 sibs from a Greek family with avascular necrosis of the femoral head (ANFH2; 617383), Mah et al. (2016) identified heterozygosity for a truncating mutation in the TRPV4 gene (V829WfsX3; 605427.0034). The mutation was not found in an unaffected brother or in public variant databases, but DNA from the sibs' parents was unavailable for study. Functional analysis in patient fibroblasts and transduced HEK293 cells indicated that the mutation results in a gain of function of TRPV4 channels by impeding channel closure. Mah et al. (2016) noted that only 2 of the previously reported TRPV4 mutations are truncating, and none are located beyond residue 799. </p><p>In a patient with nonlethal MTD, Weinstein et al. (2016) identified somatic mosaicism for a leu618-to-pro substitution (L618P; 605427.0035) in the TRPV4 gene that had previously been identified in heterozygosity by Camacho et al. (2010) in a patient with lethal MTD. </p><p><strong><em>Neuromuscular Disorders</em></strong></p><p>
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Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous mutation in the TRPV4 gene (R315W; 605427.0008). Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had congenital spinal muscular atrophy (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (originally reported by McEntagart et al., 2005). Auer-Grumbach et al. (2010) identified 2 additional TRPV4 mutations (R269H, 605427.0009 and R316C, 605427.0010) in affected members of 3 additional families with these 3 phenotypes, indicating that they are allelic disorders. All 3 mutations occurred at the outer helices of the ANK4 and ANK5 domains, in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression, as well as an impaired response to stimulus-dependent channel activity. These studies suggested that the mutations interfered with normal channel trafficking and function, resulting in haploinsufficiency. </p><p>Independently, Deng et al. (2010) and Landoure et al. (2010) identified some of the same mutations as Auer-Grumbach et al. (2010) in additional families with either SPSMA or HMSN2C, including the original families reported with the disorders (Delong and Siddique, 1992 and Dyck et al., 1994, respectively). Landoure et al. (2010) identified a novel mutation (R269C; 605427.0011) in the same protein region in another family with HMSN2C. In contrast to Auer-Grumbach et al. (2010), functional studies by Deng et al. (2010) and Landoure et al. (2010) indicated that the mutant proteins were trafficked normally, appeared at the plasma membrane, and resulted in increased calcium channel activity consistent with a gain of function. Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols. </p><p>In a family and an unrelated patient with CMT2C, Klein et al. (2011) identified 2 different heterozygous mutations in the TRPV4 gene (R232C, 605427.0025 and R316H, 605427.0026, respectively) in conserved residues in the ankyrin-repeat domain. In vitro functional expression studies showed that both mutant proteins had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant proteins caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. Klein et al. (2011) concluded that CMT2C-related mutations in this gene cause a dominant gain of function rather than haploinsufficiency. </p><p>By direct screening of the TRPV4 gene in 169 French patients with inherited axonal sensorimotor or motor peripheral neuropathy, Echaniz-Laguna et al. (2014) identified pathogenic heterozygous mutations in 12 (7%) patients. However, these 12 patients accounted for 16% of 74 patients from the entire cohort who had neuropathy with vocal cord paresis and/or skeletal dysplasia; no mutations were found in 95 patients with pure CMT2. All 12 patients had childhood-onset motor neuropathy with a variety of associated findings, including foot deformities (100%), kyphoscoliosis (100%), increased serum creatine kinase (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Six mutations occurred de novo, and 2 asymptomatic carriers were observed. The diagnoses included dHMN8 (HMND8; 600175; 7 patients), congenital spinal muscular atrophy with arthrogryposis (2 patients), scapuloperoneal spinal muscular atrophy, and CMT2C. Several of the mutations had previously been reported in patients with a spectrum of axonal neuropathies; functional studies were not performed. </p><p><strong><em>Serum Sodium Level Quantitative Trait Locus</em></strong></p><p>
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Tian et al. (2009) demonstrated that the rs3742030 SNP in the TRPV4 gene (P19S; 605427.0012) was significantly associated with serum sodium concentration (613508) and with hyponatremia, defined as serum sodium less than 135 mEq/L, in 2 non-Hispanic Caucasian male populations. In heterologous expression studies in HEK293 cells, P19S mutant channels showed diminished response to hypotonic stress and to the osmotransducing lipid epoxyeicosatrienoic acid compared to wildtype channels. Tian et al. (2009) suggested that the P19S polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis. </p><p><strong><em>Digital Arthropathy-Brachydactyly</em></strong></p><p>
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In 2 families with digital arthropathy-brachydactyly mapping to chromosome 12q24 (FDAB; 606835), Lamande et al. (2011) sequenced the candidate gene TRPV4 and identified 2 different heterozygous missense mutations that segregated with disease in each family (605427.0030 and 605427.0031). In a sporadic patient with digital arthropathy-brachydactyly, heterozygosity for a third missense mutation was identified (605427.0032). All 3 arthropathy-associated substitutions are located at highly conserved residues in TRPV4 finger loop 3 and reduce channel activity, in contrast to gain-of-function TRPV4 mutations causing skeletal dysplasias and peripheral neuropathies. </p>
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<strong>Animal Model</strong>
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<p>Suzuki et al. (2003) generated Trpv4-knockout mice by homologous recombination. The Trpv4-null mice showed reduced sensitivity of the tail to pressure and acidic nociception. Their threshold to noxious stimuli and the conduction velocity of myelinated nerve responding to stimuli were impaired, but they retained olfaction, taste sensation, and heat avoidance. The Trpv4 channel expressed in vitro in CHO cells was opened by low pH, citrate, and inflation but not by heat or capsaicin. These data identified the TRPV4 channel as essential for the normal detection of pressure and as a receptor of the high-threshold mechanosensory complex. </p><p>Gevaert et al. (2007) found that Trpv4 -/- mice had an incontinent phenotype, with a lower frequency of voiding contractions and a higher frequency of nonvoiding contractions. Relative to controls, explanted bladder strips from Trpv4 -/- mice showed reduced amplitude of spontaneous contractions, and whole bladders from Trpv4 -/- mice showed decreased intravesical stretch-evoked ATP release. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>35 Selected Examples):</strong>
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</h4>
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<span class="mim-font">
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<strong>.0001 BRACHYOLMIA TYPE 3</strong>
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TRPV4, ARG616GLN
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SNP: rs121912632,
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ClinVar: RCV000005280, RCV000202519, RCV001269634, RCV003505079
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<p>In a 5-generation pedigree segregating autosomal dominant brachyolmia type 3 (BCYM3; 113500), Rock et al. (2008) identified a c.1847G-A transition in the TRPV4 gene, resulting in an arg616-to-gln (R616Q) substitution in the fifth transmembrane region. This change was not present among 107 alleles of ancestry-matched unaffected individuals and was present in heterozygosity in all affected members of the pedigree. The mutation results in a gain of function and constitutive activation of the TRPV4 channel. R616 is conserved among human, rat, mouse, chicken, stickleback, and zebrafish proteins. </p><p>In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, Grigelioniene et al. (2014) identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene, which segregated fully with disease. </p>
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</span>
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<span class="mim-font">
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<strong>.0002 BRACHYOLMIA TYPE 3</strong>
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</h4>
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<span class="mim-text-font">
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TRPV4, VAL620ILE
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<br />
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SNP: rs121912633,
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gnomAD: rs121912633,
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ClinVar: RCV000005281, RCV000202464, RCV000202535, RCV000545248, RCV000728663, RCV001172890, RCV003992145
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<span class="mim-text-font">
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<p>In a family segregating autosomal dominant brachyolmia type 3 (BCYM3; 113500), Rock et al. (2008) identified heterozygosity for an c.858G-A transition in the TRPV4 gene, resulting in a val620-to-ile (V620I) substitution. V620 is conserved among human, rat, mouse, chicken, stickleback, and zebrafish proteins. Rock et al. (2008) found that the V620I substitution results in constitutive activation of the TRPV4 channel. </p>
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</span>
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<span class="mim-font">
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<strong>.0003 SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE</strong>
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</h4>
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<span class="mim-text-font">
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PARASTREMMATIC DWARFISM, INCLUDED<br />
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METATROPIC DYSPLASIA, INCLUDED
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</span>
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<span class="mim-text-font">
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TRPV4, ARG594HIS
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<br />
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SNP: rs77975504,
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ClinVar: RCV000005282, RCV000005283, RCV000202560, RCV000498625, RCV000691603, RCV001618207, RCV002243623, RCV002512802
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</span>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Spondylometaphyseal Dysplasia, Kozlowski Type</em></strong></p><p>
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In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition in exon 11 of the TRPV4 gene, resulting in an arg594-to-his (R594H) substitution in the cytoplasmic S4 domain. In 2 of the 4 families, the mutation was not found in DNA from the unaffected parents, establishing the change as de novo. The mutation was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. </p><p>In 12 probands with SMDK, Dai et al. (2010) identified heterozygosity for the R594H mutation and concluded that arg594 is a hotspot for mutation in SMDK. One of the patients did not show overt metaphyseal changes on x-ray and was considered to have a phenotype of intermediate severity between SMDK and brachyolmia (113500). </p><p><strong><em>Parastremmatic Dwarfism</em></strong></p><p>
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In a 7-year-old girl with parastremmatic dwarfism (168400), Nishimura et al. (2010) identified heterozygosity for the R594H mutation in the TRPV4 gene. </p><p><strong><em>Metatropic Dysplasia</em></strong></p><p>
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In a mother and 2 sons (patients 5, 6, and 7) and 2 unrelated patients (10 and 11, previously reported by Kannu et al., 2007) with metatropic dysplasia (MTD; 156530), Andreucci et al. (2011) identified heterozygosity for the R594H mutation in the TRPV4 gene. Andreucci et al. (2011) noted that the 2 sons exhibited intrafamilial variability, with one showing radiographic features that were more consistent with MTD and the other showing features more consistent with SMDK. The authors also identified heterozygosity for the R594H variant in 3 unrelated patients (patients 15, 16, and 22) clinically diagnosed with SMDK. </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>.0004 SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE</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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TRPV4, ASP333GLY
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<br />
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SNP: rs121912634,
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ClinVar: RCV000005284, RCV000202481
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified heterozygosity for a c.992A-G transition in exon 6 of the TRPV4 gene, resulting in an asp333-to-gly (N333G) substitution in the ankyrin-5 domain. The mutation, which was inherited from the proband's affected mother, was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. </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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<h4>
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<span class="mim-font">
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<strong>.0005 SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE</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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TRPV4, ALA716SER
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<br />
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SNP: rs121912635,
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ClinVar: RCV000005285, RCV000202454, RCV005089177
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with spondylometaphyseal dysplasia of the Kozlowski type (SMDK; 184252), Krakow et al. (2009) identified heterozygosity for a c.2146G-T transversion in exon 13 of the TRPV4 gene, resulting in an ala716-to-ser (A716S) substitution in the cytoplasmic S6 domain. The mutation occurred de novo and was not associated with increased basal intracellular calcium ion concentration or intracellular activity when compared with wildtype. The mutation occurs in a highly conserved residue and was not found in at least 214 control chromosomes. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 METATROPIC DYSPLASIA</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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TRPV4, ILE331PHE
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<br />
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SNP: rs121912636,
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gnomAD: rs121912636,
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ClinVar: RCV000005286, RCV000202518
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with metatropic dysplasia (MTD; 156530), Krakow et al. (2009) identified heterozygosity for a c.1080A-T transversion in exon 6 of the TRPV4 gene, resulting in an ile331-to-phe (I331F) substitution in the ankyrin-5 domain. The mutation occurs in a highly conserved residue and was not identified in the unaffected parents or in at least 214 control chromosomes. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
By in vitro functional expression studies in HEK cells, Camacho et al. (2010) showed that the I331F-mutant protein had larger basal currents with constitutive open channels compared to wildtype. Treatment with agonists resulted in even larger calcium currents and increased intracellular calcium levels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 METATROPIC DYSPLASIA</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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SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TRPV4, PRO799LEU
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<br />
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SNP: rs121912637,
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|
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ClinVar: RCV000005287, RCV000005288, RCV000202554, RCV000624630, RCV000707315, RCV001253672, RCV001311314, RCV003388565
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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 />
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<p><strong><em>Metatropic Dysplasia</em></strong></p><p>
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In a patient with metatropic dysplasia (MTD; 156530), Krakow et al. (2009) identified heterozygosity for a c.2396C-T transition in exon 15 of the TRPV4 gene, resulting in a pro799-to-leu substitution in the cytoplasmic domain. The mutation, which occurs in a highly conserved residue, was not identified in the unaffected parents or in at least 214 control chromosomes. </p><p>In 9 probands with MTD, Dai et al. (2010) identified heterozygosity for the P799L mutation. Four more MTD patients had 3 different substitutions at pro799 (see 605427.0013-605427.0015), leading Dai et al. (2010) to designate it as a 'hot codon' for MTD mutations. </p><p>Camacho et al. (2010) reported 2 unrelated patients with metatropic dysplasia who were heterozygous for the P799L mutation. Each had a nonlethal but moderately severe form of the disorder, with scoliosis, platyspondyly with irregular endplates, widened irregular metaphyses, and marked epiphyseal delay. In vitro functional expression studies in HEK cells showed that the P799L-mutant protein had larger basal currents with constitutive open channels compared to wildtype. Treatment with agonists resulted in even larger calcium currents and increased intracellular calcium levels. </p><p>In 5 patients with MTD (patients 2, 3, 4, 12, and 13), including 3 patients previously reported by Kannu et al. (2007) (patients 2, 3, and 4), Andreucci et al. (2011) identified heterozygosity for the P799L variant in the TRPV4 gene. Patients 2 and 3 were a father/daughter pair; the father was originally described by Beck et al. (1983). </p><p><strong><em>Spondyloepiphyseal Dysplasia, Maroteaux Type</em></strong></p><p>
|
|
In 2 unrelated patients with the Maroteaux type of spondyloepiphyseal dysplasia (184095), 1 of whom was a girl previously reported by Megarbane et al. (2004), Nishimura et al. (2010) identified heterozygosity for the P799L mutation in the TRPV4 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
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SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY, INCLUDED<br />
|
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HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TRPV4, ARG315TRP
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<br />
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SNP: rs267607143,
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|
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ClinVar: RCV000005289, RCV000005290, RCV000005291, RCV000202514, RCV000236487, RCV000789585, RCV002371762, RCV003335013, RCV004547459
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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>Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous c.943C-T transition in exon 6 of the TRPV4 gene, resulting in an arg315-to-trp (R315W) substitution. Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had distal hereditary motor neuropathy, type VIII (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (McEntagart et al., 2005). The mutation was not found in 304 control individuals. The R315W mutation occurred at the outer helices of the ANK4 and ANK5 domains in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies indicated that the mutation interferes with normal channel trafficking and function. Haploinsufficiency was proposed as the most likely underlying mechanism, although a gain of function could not be fully excluded. </p><p>Chen et al. (2010) identified a heterozygous R315W mutation in a 47-year-old mother and her 26-year-old daughter with HMSN2C and vocal cord paresis; the family had originally been reported by Dyck et al. (1994). Both patients had onset in infancy and developed a relatively severe form of distal muscle weakness and distal sensory loss, as well as short stature. </p><p>Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous R315W TRPV4 mutation. Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit. </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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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, ARG269HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607144,
|
|
|
|
|
|
|
|
ClinVar: RCV000005292, RCV000005293, RCV000192243, RCV000202467, RCV000235740, RCV000623703, RCV000763296, RCV003320352
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|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Distal Hereditary Motor Neuropathy 8, Autosomal Dominant</em></strong></p><p>
|
|
In affected members of a large family in which 20 individuals had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175), Auer-Grumbach et al. (2010) identified a heterozygous c.806G-A transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-his (R269H) substitution. The family had originally been reported by Fleury and Hageman (1985). The mutation was not found in 162 European control individuals. The mutation occurred at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency. </p><p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
|
|
In affected members of the family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071) reported by Dyck et al. (1994), Deng et al. (2010) and Landoure et al. (2010) independently identified a heterozygous R269H mutation in the TRPV4 gene. Deng et al. (2010) did not find the mutation in over 700 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. Deng et al. (2010) postulated a gain-of-function mechanism. The studies of Landoure et al. (2010) showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269C; 605427.0011). </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols. </p><p>By in vitro functional expression studies, Klein et al. (2011) showed that the mutant R269H protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations in HEK293 cells compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The findings were consistent with a pathogenic gain of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, ARG316CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607145,
|
|
|
|
|
|
|
|
ClinVar: RCV000005294, RCV000005295, RCV000192245, RCV000202561, RCV000236285, RCV000789587, RCV001796956, RCV002371763
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
|
|
In 3 affected members of a family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), Auer-Grumbach et al. (2010) identified a heterozygous c.946C-T transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-cys (R316C) substitution. The mean age at onset was 3 years, with distal lower limb muscle weakness and wasting, areflexia, and vocal cord paralysis. The R316C mutation was also found in 3 affected individuals in another family: 1 had a phenotype of HMSN2C and 2 others had a phenotype consistent with scapuloperoneal spinal muscular atrophy (181405). The mean age at onset was 29.2 years, with distal upper and lower limb muscle weakness, atrophy, and areflexia. One patient had scoliosis, 1 had proximal muscle involvement, 1 had sensory symptoms, and 1 had vocal cord paresis. The mutation was not found in 304 European control individuals. The mutation occurs at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency. </p><p><strong><em>Scapuloperoneal Spinal Muscular Atrophy</em></strong></p><p>
|
|
Deng et al. (2010) identified a heterozygous R316C mutation in affected members of a large family with autosomal dominant scapuloperoneal spinal muscular atrophy reported by DeLong and Siddique (1992). The mutation was not found in 600 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. Deng et al. (2010) postulated a gain-of-function mechanism. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8, INCLUDED<br />
|
|
SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, ARG269CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607146,
|
|
|
|
|
|
gnomAD: rs267607146,
|
|
|
|
|
|
ClinVar: RCV000005296, RCV000033215, RCV000190885, RCV000202537, RCV000517563, RCV000856933, RCV001027476, RCV002415400
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with hereditary motor and sensory neuropathy IIC (HMSN2C; 606071), Landoure et al. (2010) identified a heterozygous c.805C-T transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-cys (R269C) substitution. In vitro functional expression studies showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269H; 605427.0009). </p><p><strong><em>Scapuloperoneal Spinal Muscular Atrophy and Autosomal Dominant Distal Hereditary Motor Neuropathy 8</em></strong></p><p>
|
|
Berciano et al. (2011) reported a family in which 2 of 5 individuals carrying the same heterozygous R269C mutation had different phenotypes: a 44-year-old woman had scapuloperoneal spinal muscular atrophy (SPSMA; 181405) and her 7-year-old daughter had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175). The 3 other individuals with the mutation were clinically and electrophysiologically asymptomatic 9, 40, and 70 years of age, respectively, consistent with incomplete penetrance. The mother had sloped shoulders since childhood and later developed progressive lower leg muscle weakness and atrophy. She also had transient dysphonia. Muscle biopsy showed evidence of chronic denervation and renervation, and electrophysiologic studies showed reduced compound muscle action potentials with normal nerve conduction velocities, consistent with a motor axonal neuropathy. The daughter was born with congenital arthrogryposis and showed delayed motor development and laryngomalacia with stridor and vocal cord paresis necessitating intermittent tracheostomy placement. She was wheelchair-bound at age 7 due to limited joint mobility and lower limb muscle weakness, and also had weakness and atrophy of the shoulder girdle muscles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 SODIUM SERUM LEVEL QUANTITATIVE TRAIT LOCUS 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, PRO19SER ({dbSNP rs3742030})
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|
|
|
<br />
|
|
|
|
SNP: rs3742030,
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|
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|
|
|
gnomAD: rs3742030,
|
|
|
|
|
|
ClinVar: RCV000005297, RCV000125613, RCV000259885, RCV000277523, RCV000317460, RCV000357119, RCV000388208, RCV000713884, RCV001079400, RCV001172934, RCV002276532
|
|
|
|
|
|
</span>
|
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</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 cohorts of elderly individuals, Tian et al. (2009) found that a pro19-to-ser (P19S) polymorphism in the TRPV4 gene (rs3742030) was significantly associated with serum sodium concentration (613508) and with hyponatremia, defined as serum sodium less than 135 mEq/L, in non-Hispanic Caucasian males. Mean serum sodium concentration was lower among subjects with the 19S allele relative to the wildtype 19P allele, and subjects with the minor allele were 2.4 to 6.4 times as likely to exhibit hyponatremia as subjects without the minor allele. Heterologous expression studies in HEK293 cells showed that P19S mutant channels showed diminished response to hypotonic stress and to the osmotransducing lipid epoxyeicosatrienoic acid compared to wildtype channels. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, PRO799ALA
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|
|
|
|
<br />
|
|
|
|
SNP: rs267607147,
|
|
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|
|
|
|
|
ClinVar: RCV000005298
|
|
|
|
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</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a c.2395C-G transversion in exon 15 of the TRPV4 gene, resulting in a pro799-to-ala (P799A) substitution at an evolutionarily conserved residue in the cytoplasmic domain. Dai et al. (2010) noted that pro799 appeared to be a 'hot codon' for MTD mutations (see 605427.0007, 605427.0014, and 605427.0015). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, PRO799SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607147,
|
|
|
|
|
|
|
|
ClinVar: RCV000005299, RCV000202484
|
|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a c.2395C-T transition in exon 15 of the TRPV4 gene, resulting in a pro799-to-ser (P799S) substitution at an evolutionarily conserved residue in the cytoplasmic domain. Dai et al. (2010) noted that pro799 appeared to be a 'hot codon' for MTD mutations (see 605427.0007, 605427.0013, and 605427.0015). </p><p>In a female infant (patient 8) who died at age 4.5 months with MTD, Andreucci et al. (2011) identified heterozygosity for the P799S variant in the TRPV4 gene. The patient was hospitalized immediately after birth due to skeletal malformations and respiratory difficulties. She had severe cervical instability, and her death was believed to be caused by medullary compression and respiratory decompensation. </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>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0015 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
TRPV4, PRO799ARG
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<br />
|
|
|
|
SNP: rs121912637,
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|
|
|
|
|
ClinVar: RCV000005300, RCV000202509, RCV005089285
|
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|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a c.2396C-G transversion in exon 15 of the TRPV4 gene, resulting in a pro799-to-arg (P799R) substitution at an evolutionarily conserved residue in the cytoplasmic domain. Dai et al. (2010) noted that pro799 appeared to be a 'hot codon' for MTD mutations (see 605427.0007, 605427.0013, and 605427.0014). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
TRPV4, 3-BP DEL, 1411TTC
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<br />
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|
|
SNP: rs515726154,
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|
|
ClinVar: RCV000202564, RCV000756825, RCV001376047, RCV002279715, RCV003505097
|
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|
|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a 3-bp deletion (c.1411delTTC) in exon 8 of the TRPV4 gene, resulting in deletion of phe471 (F471del) from the S1 domain. The authors stated that this was the first reported mutation other than a missense mutation in the TRPV4 gene. </p><p>In a patient with lethal infantile metatropic dysplasia, Camacho et al. (2010) identified heterozygosity for the F471del mutation, which they described as affecting nucleotides 1412 to 1414. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE</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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|
|
|
TRPV4, GLU278LYS
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|
<br />
|
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|
|
SNP: rs267607148,
|
|
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|
|
|
|
ClinVar: RCV000005302, RCV000202563, RCV000805229
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for an c.832G-A transition in exon 5 of the TRPV4 gene, resulting in a glu278-to-lys (E278K) substitution at an evolutionarily conserved residue in the ANK3 domain. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE, INCLUDED<br />
|
|
METATROPIC DYSPLASIA, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, GLU797LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607149,
|
|
|
|
|
|
|
|
ClinVar: RCV000005303, RCV000005304, RCV000023424, RCV000202566, RCV001331193, RCV001549550, RCV001823100, RCV001851964
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Spondylometaphyseal Dysplasia, Kozlowski Type</em></strong></p><p>
|
|
In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A transition in exon 15 of the TRPV4 gene, resulting in a glu797-to-lys (E797K) substitution at an evolutionarily conserved residue in the cytoplasmic domain. The authors noted that this was the first SMDK patient to be reported with a mutation in exon 15, which otherwise appears to be a hotspot for mutations causing metatropic dysplasia (MTD; 156530). </p><p><strong><em>Spondylometaphyseal Dysplasia, Maroteaux Type</em></strong></p><p>
|
|
In an adult woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for the E797K mutation in the TRPV4 gene. </p><p><strong><em>Metatropic Dysplasia</em></strong></p><p>
|
|
Camacho et al. (2010) identified a heterozygous E797K mutation in a patient with a mild form of metatropic dysplasia (MTD; 156530), with little or no scoliosis, mild platyspondyly, mild metaphyseal widening, and carpal ossification delay. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, 17-BP DEL, NT2396
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs515726166,
|
|
|
|
|
|
|
|
ClinVar: RCV000202488, RCV002279935
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), previously reported by Nishimura et al. (2003), Nishimura et al. (2010) identified heterozygosity for a 17-bp deletion (c.2396del17) in the TRPV4 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, GLU183LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906324,
|
|
|
|
|
|
|
|
ClinVar: RCV000005306, RCV000202438, RCV001851965
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese man with the Maroteaux type of spondyloepiphyseal dysplasia (184095), previously reported by Nishimura et al. (2003), Nishimura et al. (2010) identified heterozygosity for a c.647G-A transition in exon 3 of the TRPV4 gene, resulting in a glu183-to-lys (E183K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, TYR602CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607150,
|
|
|
|
|
|
|
|
ClinVar: RCV000023425, RCV000202448
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6.5-year-old boy from a 4-generation family with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for a c.1805A-G transition in exon 11 of the TRPV4 gene, resulting in a tyr602-to-cys (Y602C) substitution. His mother, maternal grandfather, and great-grandmother were also affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, SER542TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906902,
|
|
|
|
|
|
gnomAD: rs387906902,
|
|
|
|
|
|
ClinVar: RCV000023426, RCV000202508
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), Chen et al. (2010) identified a heterozygous c.1625C-A transversion in exon 10 of the TRPV4 gene, resulting in a ser542-to-tyr (S542Y) substitution in the transmembrane domain. The mutation was not found in 400 control chromosomes. The distal sensory loss and muscle weakness in this family was relatively mild, and all but 1 patient had vocal cord paresis. In addition, affected individuals had proportional short stature, which was more pronounced in females, and 1 had dolichocephaly. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, THR89ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514473,
|
|
|
|
|
|
|
|
ClinVar: RCV000023427, RCV000202521, RCV004549386
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with lethal neonatal metatropic dysplasia (MTD; 156530), Camacho et al. (2010) identified heterozygosity for a c.366C-T transition in exon 2 of the TRPV4 gene, resulting in a thr89-to-ile (T89I) substitution in the N-terminal cytoplasmic domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, LYS197ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906903,
|
|
|
|
|
|
|
|
ClinVar: RCV000023428, RCV000202524, RCV001315769
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with lethal infantile metatropic dysplasia (MTD; 156530), Camacho et al. (2010) identified heterozygosity for a c.590A-G transition in exon 4 of the TRPV4 gene, resulting in a lys197-to-arg (K197R) substitution in the ANK2 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, ARG232CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906904,
|
|
|
|
|
|
|
|
ClinVar: RCV000023429, RCV000190886, RCV000202445, RCV000236017, RCV000789594, RCV001172888, RCV001542600
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
|
|
In a family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071) originally reported by Donaghy and Kennett (1999), Klein et al. (2011) identified a heterozygous c.694C-T transition in exon 4 of the TRPV4 gene, resulting in an arg232-to-cys (R232C) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls. </p><p><strong><em>Distal Hereditary Motor Neuronopathy 8, Autosomal Dominant</em></strong></p><p>
|
|
Astrea et al. (2012) identified an R232C mutation in an 11-year-old girl with autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175). She had proximal and distal muscle weakness, atrophy of the distal leg muscles, and clubfoot. MRI of the thighs and calf muscles showed extensive fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves. This pattern was distinct when compared to a patient with non-TRPV4 spinal muscular atrophy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, ARG316HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906905,
|
|
|
|
|
|
|
|
ClinVar: RCV000023430, RCV000202476, RCV000415397, RCV000497541, RCV000856932
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 30-year-old man with HMSN2C (606071), Klein et al. (2011) identified a de novo heterozygous c.947G-A transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-his (R316H) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls. </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>
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<h4>
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<span class="mim-font">
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<strong>.0027 METATROPIC DYSPLASIA</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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TRPV4, GLY78TRP
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<br />
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SNP: rs397514474,
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ClinVar: RCV000023431, RCV000202458
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 21-week-old fetus with severe metatropic dysplasia (MTD; 156530) and fetal akinesia, Unger et al. (2011) identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a gly78-to-trp (G78W) substitution in a conserved residue. Prenatal ultrasound at age 20 weeks' gestation showed short long bones, narrow bell-shaped thorax, finger contractures, and undetectable fetal movements. After termination, the fetus was found to have short long bones with mildly accentuated metaphyses, cartilaginous expansions of the elbow, wrist, and knee joints, relatively long hands and feet, and flattened vertebral bodies. Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in this patient, and suggested that this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0028 METATROPIC DYSPLASIA</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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TRPV4, THR740ILE
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<br />
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SNP: rs387906906,
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ClinVar: RCV000023432, RCV000202544
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a pair of 20-week-old monozygotic twins with severe metatropic dysplasia (MTD; 156530) and fetal akinesia, Unger et al. (2011) identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a thr740-to-ile (T740I) substitution in a conserved residue. Absence of fetal movements with arthrogryposis was detected on prenatal ultrasound. Both fetuses had short long bones, thoracic hypoplasia, a sacrococcygeal tail, and contractures. Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and suggested that this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0029 METATROPIC DYSPLASIA</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TRPV4, LYS276GLU
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<br />
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SNP: rs387906907,
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ClinVar: RCV000023433, RCV000202517, RCV000413499
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male infant, born of consanguineous Algerian parents, with severe metatropic dysplasia (MTD; 156530), Unger et al. (2011) identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a lys276-to-glu (K276E) substitution in a conserved residue. The mother noted diminished fetal movements during pregnancy, which was confirmed by ultrasound. At birth the infant was noted to have severe contractures consistent with fetal akinesia syndrome, thoracic hypoplasia, clubfeet, camptodactyly, and enlarged joints. Radiographs confirmed metatropic dysplasia. The legs could not be straightened and remained in a flexed and adducted position. Although neonatal neurologic examination was normal, except for restricted movements, electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in this patient, and since electrophysiologic studies indicated a neuropathic process, this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. </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>.0030 DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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TRPV4, PHE273LEU
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<br />
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SNP: rs515726170,
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ClinVar: RCV000202455
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In all affected members of a family with digital arthropathy-brachydactyly (FDAB; 606835), originally reported by Amor et al. (2002), Lamande et al. (2011) identified heterozygosity for an c.819C-G transversion in exon 5 of the TRPV4 gene, resulting in a phe273-to-leu (F273L) substitution at a highly conserved residue within finger loop 3. The mutation was not found in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
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TRPV4, ARG271PRO
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<br />
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|
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SNP: rs387907219,
|
|
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|
|
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gnomAD: rs387907219,
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|
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ClinVar: RCV000029173
|
|
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|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In all 5 affected members of a family with digital arthropathy-brachydactyly (FDAB; 606835), Lamande et al. (2011) identified heterozygosity for an c.812G-C transversion in exon 5 of the TRPV4 gene, resulting in an arg271-to-pro (R271P) substitution at a highly conserved residue within finger loop 3. The mutation was not found in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
TRPV4, GLY270VAL
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<br />
|
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|
|
SNP: rs387907220,
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|
|
ClinVar: RCV000029174
|
|
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|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with digital arthropathy-brachydactyly (FDAB; 606835), Lamande et al. (2011) identified heterozygosity for an c.809G-T transversion in exon 5 of the TRPV4 gene, resulting in a gly270-to-val (G270V) substitution at a highly conserved residue within finger loop 3. The mutation was not found in the patient's unaffected sister or in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 8, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, ARG186GLN
|
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|
|
<br />
|
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|
|
SNP: rs397514494,
|
|
|
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|
|
ClinVar: RCV000032600, RCV000190887, RCV000202485, RCV000235384, RCV001265863
|
|
|
|
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Hereditary Motor and Sensory Neuropathy Type IIC</em></strong></p><p>
|
|
In 3 members of a family with HMSN2C (606071), Landoure et al. (2012) identified a heterozygous c.557G-A transition in the TRPV4 gene, resulting in an arg186-to-gln (R186Q) substitution at a highly conserved residue situated on the convex face of the ankyrin repeat domain (ARD). The mutation was found by exome sequencing and confirmed by Sanger sequencing. This family had previously been reported as family 3 in Landoure et al. (2010), but the primers used in that study did not identify the TRPV4 mutation. Functional expression studies in HEK293 cells showed that the R186Q mutant protein resulted in increased calcium levels and increased cell death, suggesting abnormal constitutive TRPV4 activity, as observed with the R269C (605427.0011) mutant. The patients had progressive distal limb muscle weakness and atrophy, hoarse voice, and stridor on exertion. Nerve conduction studies confirmed an axonal neuropathy with phrenic nerve involvement. Two patients had scoliosis and 1 had sensorineural hearing loss, but none had skeletal dysplasia. </p><p><strong><em>Distal Hereditary Motor Neuronopathy Type VIII</em></strong></p><p>
|
|
Echaniz-Laguna et al. (2014) identified a heterozygous R186Q mutation in a child with autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175). The patient's unaffected mother also carried the mutation, consistent with incomplete penetrance. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 AVASCULAR NECROSIS OF FEMORAL HEAD, PRIMARY, 2 (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, 4-BP DEL, 2480CCCG AND 2486T-A
|
|
|
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|
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<br />
|
|
|
|
SNP: rs1057520305,
|
|
|
|
|
|
|
|
ClinVar: RCV000435546
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 sibs from a Greek family with avascular necrosis of the femoral head (ANFH2; 617383), Mah et al. (2016) identified heterozygosity for a 4-bp deletion (c.2480_2483delCCCG, NM_021625.4) followed by a c.2486T-A transversion (c.2486T-A, NM_021625.4) in a highly conserved region of the TRPV4 gene, causing a frameshift that results in a premature termination codon (Val829TrpfsTer3). The mutation was not found in an unaffected brother, or in the 1000 Genomes or Exome Variant Server databases; parental DNA was unavailable, but the sibs' father reportedly had symptoms of joint pain that were never evaluated. Functional analysis in patient fibroblasts and transduced HEK293 cells indicated that the mutation results in a gain-of-function of TRPV4 channels by impeding channel closure. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 METATROPIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPV4, LEU618PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs515726163,
|
|
|
|
|
|
|
|
ClinVar: RCV000202495, RCV000497423, RCV000755170
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (R09-035) with a neonatal lethal form of metatropic dysplasia (MTD; 156530), Camacho et al. (2010) identified heterozygosity for an c.1853T-C transition in exon 12 of the TRPV4 gene that resulted in a leu618-to-pro (L618P) substitution at a highly evolutionarily conserved amino acid residue in transmembrane segment 5 (TM5). </p><p>In a patient (R09-440A) with nonlethal MTD, Weinstein et al. (2016) detected somatic mosaicism for the L618P mutation in TRPV4 previously identified by Camacho et al. (2010). Sanger sequencing was negative for mutations in all of the coding exons of TRPV4, as well as of other genes consistent with the phenotype. Subsequent exome sequencing detected a c.1853T-C transition in 16 of 71 reads, consistent with somatic mosaicism. Parental exomes were negative for the mutation. Comparison of the levels of the mutant allele in this patient with those of the patient of Camacho et al. (2010) showed that 15% of alleles in blood cells contained the mutation, implying that about 30% of cells in the patient would be expected to be heterozygous for the L618P allele. However, the level of mosaicism in the target tissue (cartilage) could not be assessed directly because a sample was not available. Weinstein et al. (2016) noted that high-throughput sequencing can have higher sensitivity for the detection of mosaicism than Sanger sequence analysis. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aharoni, S., Harlalka, G., Offiah, A., Shuper, A., Crosby, A. H., McEntagart, M.
|
|
<strong>Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorder.</strong>
|
|
Am. J. Med. Genet. 155A: 3153-3156, 2011.
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|
|
[PubMed: 22065612]
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[Full Text: https://doi.org/10.1002/ajmg.a.34327]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Amor, D. J., Tudball, C., Gardner, R. J. M., Lamande, S. R., Bateman, J. F., Savarirayan, R.
|
|
<strong>Familial digital arthropathy-brachydactyly.</strong>
|
|
Am. J. Med. Genet. 108: 235-240, 2002.
|
|
|
|
|
|
[PubMed: 11891693]
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|
|
[Full Text: https://doi.org/10.1002/ajmg.10269]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R.
|
|
<strong>TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families.</strong>
|
|
Orphanet J. Rare Dis. 6: 37, 2011.
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|
|
[PubMed: 21658220]
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|
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[Full Text: https://doi.org/10.1186/1750-1172-6-37]
|
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</p>
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|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Astrea, G., Brisca, G., Fiorillo, C., Valle, M., Tosetti, M., Bruno, C., Santorelli, F. M., Battini, R.
|
|
<strong>Muscle MRI in TRPV4-related congenital distal SMA.</strong>
|
|
Neurology 78: 364-365, 2012.
|
|
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|
|
[PubMed: 22291064]
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|
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[Full Text: https://doi.org/10.1212/WNL.0b013e318245295a]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others.
|
|
<strong>Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.</strong>
|
|
Nature Genet. 42: 160-164, 2010.
|
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|
|
[PubMed: 20037588]
|
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|
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[Full Text: https://doi.org/10.1038/ng.508]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Beck, M., Roubicek, M., Rogers, J. G., Naumoff, P., Spranger, J.
|
|
<strong>Heterogeneity of metatropic dysplasia.</strong>
|
|
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Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., Plant, T. D.
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