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Entry
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- *173910 - POLYCYSTIN 2; PKD2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*173910</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/173910">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<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=ENSG00000118762;t=ENST00000237596" 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=5311" 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=173910" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</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=ENSG00000118762;t=ENST00000237596" 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_000297,NR_156488,XM_011532028,XM_011532029,XM_011532030" 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_000297" 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=173910" 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=01437&isoform_id=01437_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/PKD2" 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/1373169,1477692,3005706,3126905,4505835,10281555,85567393,85567685,116242717,119626416,194373721,194376696,221040114,758838807,758838809,767932098,767932100,767932102,2462597545,2462597547,2462597549" 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/Q13563" 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=5311" 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=ENSG00000118762;t=ENST00000237596" 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=PKD2" 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=PKD2" 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+5311" 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/PKD2" 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:5311" 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/5311" 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=chr4&hgg_gene=ENST00000237596.7&hgg_start=88007635&hgg_end=88077777&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9009" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9009" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/pkd2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=173910[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=173910[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000118762" 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=PKD2" 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=PKD2" 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=PKD2" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://pkdb.mayo.edu/" title="Autosomal Dominant Polycystic Kidney Disease: Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Autosomal Dominant Polycys…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/PKD2" title="Autosomal Dominant Polycystic Kidney Disease (ADPKD)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Autosomal Dominant Polycys…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PKD2&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/PA33343" 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:9009" 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/FBgn0041195.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:1099818" 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/PKD2#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:1099818" 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/5311/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/OMIA002525/" 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=5311" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004035;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040827-4" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=PKD2&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> 253879006<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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173910
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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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POLYCYSTIN 2; PKD2
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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">
|
|
PKD2 GENE<br />
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PC2<br />
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TRPP2
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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=PKD2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PKD2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/4/398?start=-3&limit=10&highlight=398">4q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:88007635-88077777&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'})">4:88,007,635-88,077,777</a> </span>
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<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">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</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>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/398?start=-3&limit=10&highlight=398">
|
|
4q22.1
|
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</a>
|
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</span>
|
|
</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Polycystic kidney disease 2
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613095"> 613095 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<p>The PKD2 gene encodes polycystin-2, which belongs to the superfamily of transient receptor potential (TRP) channels. Polycystin-2 is a large-conductance, Ca(2+)-permeable nonselective cation channel involved in Ca(2+) transport and Ca(2+) signaling in renal epithelial cells (<a href="#59" class="mim-tip-reference" title="Zhang, P., Luo, Y., Chasan, B., Gonzalez-Perrett, S., Montalbetti, N., Timpanaro, G. A., del Rocio Cantero, M., Ramos, A. J., Goldmann, W. H., Zhou, J., Cantiello, H. F. <strong>The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1.</strong> Hum. Molec. Genet. 18: 1238-1251, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19193631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19193631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19193631[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/10.1093/hmg/ddp024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19193631">Zhang et al., 2009</a>). PKD2 localizes to cilia and functions as a mechanotransducer that stimulates an increase in intracellular calcium in response to fluid flow (<a href="#32" class="mim-tip-reference" title="Nauli, S. M., Alenghat, F. J, Luo, Y., Williams, E., Vassilev, P., Li, X., Elia, A. E. H., Lu, W., Brown, E. M., Quinn, S. J., Ingber, D. E., Zhou, J. <strong>Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.</strong> Nature Genet. 33: 129-137, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514735</a>] [<a href="https://doi.org/10.1038/ng1076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514735">Nauli et al., 2003</a>). Like other prototypical TRP channels, polycystin-2 has 6 transmembrane domains and cytoplasmic N and C termini. TRP channels, including polycystin-2, assemble as homo- and heteromultimers, particularly tetramers, and this heteromerization is thought to provide functional and regulatory diversity among channel complexes (<a href="#59" class="mim-tip-reference" title="Zhang, P., Luo, Y., Chasan, B., Gonzalez-Perrett, S., Montalbetti, N., Timpanaro, G. A., del Rocio Cantero, M., Ramos, A. J., Goldmann, W. H., Zhou, J., Cantiello, H. F. <strong>The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1.</strong> Hum. Molec. Genet. 18: 1238-1251, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19193631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19193631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19193631[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/10.1093/hmg/ddp024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19193631">Zhang et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19193631+12514735" 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="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> reported the isolation and characterization of a candidate gene for polycystic kidney disease-2 (PKD2; <a href="/entry/613095">613095</a>) on chromosome 4. They initially refined the mapping of the PKD2 gene within an interval of 680 kb. They then used genomic clones from this interval to isolate cDNA clones. One of these clones revealed homology at the amino acid level with polycystin, the PKD1 gene product (<a href="/entry/601313">601313</a>). This clone was used to isolate a series of overlapping cDNA clones that encompassed the candidate gene. The gene contains a 2,904-bp open reading frame and a 2,086-bp untranslated region. It is strongly expressed in ovary, fetal and adult kidney, testis, and small intestine. <a href="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> detected no expression of the gene in peripheral leukocytes. The predicted translation product is a 968-amino acid polypeptide which appears to be an integral membrane protein with 6 membrane-spanning domains and intracellular N and C termini. There is 25% identity and 50% similarity between the putative translation product of PKD2 and the 450-amino acid product of PKD1. There is a similar degree of homology between the putative PKD2 locus product and that of the voltage-activated calcium channel-alpha-1E gene (see <a href="/entry/601012">601012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" 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="#44" class="mim-tip-reference" title="Schneider, M. C., Rodriguez, A. M., Nomura, H., Zhou, J., Morton, C. C., Reeders, S. T., Weremowicz, S. <strong>A gene similar to PKD1 maps to chromosome 4q22: a candidate gene for PKD2.</strong> Genomics 38: 1-4, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954772</a>] [<a href="https://doi.org/10.1006/geno.1996.0584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954772">Schneider et al. (1996)</a> likewise cloned the PKD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954772" 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="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> determined that the PKD2 gene extends over 68 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Hayashi, T., Mochizuki, T., Reynolds, D. M., Wu, G., Cai, Y., Somlo, S. <strong>Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2).</strong> Genomics 44: 131-136, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9286709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9286709</a>] [<a href="https://doi.org/10.1006/geno.1997.4851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9286709">Hayashi et al. (1997)</a> found that the PKD2 gene has at least 15 exons with the translation start site in exon 1. All the splice acceptor and donor sites conform to the AG/GT rule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9286709" 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="Lantinga-van Leeuwen, I. S., Leonhard, W. N., Dauwerse, H., Baelde, H. J., van Oost, B. A., Breuning, M. H., Peters, D. J. M. <strong>Common regulatory elements in the polycystic kidney disease 1 and 2 promoter regions.</strong> Europ. J. Hum. Genet. 13: 649-659, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15770226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15770226</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15770226">Lantinga-van Leeuwen et al. (2005)</a> determined that the promoter region of both the PKD1 and PKD2 genes are TATA-less, but they have binding sites for E2F (see <a href="/entry/189971">189971</a>), EGRF (see EGR1; <a href="/entry/128990">128990</a>), ETS (see <a href="/entry/600541">600541</a>), MZF1 (<a href="/entry/194550">194550</a>), SP1 (<a href="/entry/189906">189906</a>), and ZBP89 (<a href="/entry/601867">601867</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15770226" 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="#46" class="mim-tip-reference" title="Su, Q., Hu, F., Ge, X., Lei, J., Yu, S., Wang, T., Zhou, Q., Mei, C., Shi, Y. <strong>Structure of the human PKD1-PKD2 complex.</strong> Science 361: eaat9819, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30093605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30093605</a>] [<a href="https://doi.org/10.1126/science.aat9819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30093605">Su et al. (2018)</a> reported the 3.6-angstrom cryoelectron microscopy structure of truncated human PKD1 (<a href="/entry/601313">601313</a>)-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical transient receptor potential channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the voltage-gated ion channel, a 5-transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30093605" 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>Using a YAC contig and STS map of the PKD2 region on chromosome 4, <a href="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> mapped the PKD2 gene to chromosome 4q21-q23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" 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>It was suggested that the different forms of autosomal dominant polycystic kidney disease, PKD1 and PKD2, and perhaps a third form result from defects in interactive factors involved in a common pathway. The discovery of the genes for the 2 most common forms of ADPKD provided an opportunity to test this hypothesis. <a href="#39" class="mim-tip-reference" title="Qian, F., Germino, F. J., Cai, Y., Zhang, X., Somlo, S., Germino, G. G. <strong>PKD1 interacts with PKD2 through a probable coiled-coil domain.</strong> Nature Genet. 16: 179-183, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171830</a>] [<a href="https://doi.org/10.1038/ng0697-179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171830">Qian et al. (1997)</a> described a previously unrecognized coiled-coil domain within the C terminus of the PKD1 gene product, polycystin-1, and demonstrated that it binds specifically to the C terminus of PKD2. Homotypic interactions involving the C terminus of each were also demonstrated. They showed that naturally occurring pathogenic mutations of PKD1 and PKD2 disrupt their associations. <a href="#39" class="mim-tip-reference" title="Qian, F., Germino, F. J., Cai, Y., Zhang, X., Somlo, S., Germino, G. G. <strong>PKD1 interacts with PKD2 through a probable coiled-coil domain.</strong> Nature Genet. 16: 179-183, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171830</a>] [<a href="https://doi.org/10.1038/ng0697-179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171830">Qian et al. (1997)</a> suggested that PKD1 and PKD2 associate physically in vivo and may be partners of a common signaling cascade involved in tubular morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171830" 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="#49" class="mim-tip-reference" title="Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V. P., Walz, G. <strong>Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.</strong> Proc. Nat. Acad. Sci. 94: 6965-6970, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9192675[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.94.13.6965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192675">Tsiokas et al. (1997)</a> showed that PKD1 and PKD2 interact through their C-terminal cytoplasmic tails. This interaction results in upregulation of PKD1 but not PKD2. Furthermore, the cytoplasmic tail of PKD2 but not PKD1 forms homodimers through a coiled-coil domain distinct from the region required for interaction with PKD1. These interactions suggested that PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis and that PKD1 requires the presence of PKD2 for stable expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192675" 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>PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell-to-cell or cell-matrix interactions, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein. <a href="#14" class="mim-tip-reference" title="Hanaoka, K., Qian, F., Boletta, A., Bhunia, A. K., Piontek, K., Tsiokas, L., Sukhatme, V. P., Guggino, W. B., Germino, G. G. <strong>Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.</strong> Nature 408: 990-994, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140688</a>] [<a href="https://doi.org/10.1038/35050128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140688">Hanaoka et al. (2000)</a> demonstrated that polycystin-1 and -2 interact to produce new calcium-permeable nonselective cation currents. Neither polycystin-1 nor polycystin-2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization through the coiled-coil domain do not result in new channel activity. <a href="#14" class="mim-tip-reference" title="Hanaoka, K., Qian, F., Boletta, A., Bhunia, A. K., Piontek, K., Tsiokas, L., Sukhatme, V. P., Guggino, W. B., Germino, G. G. <strong>Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.</strong> Nature 408: 990-994, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140688</a>] [<a href="https://doi.org/10.1038/35050128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140688">Hanaoka et al. (2000)</a> also showed that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 coassemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11140688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Koulen, P., Cai, Y., Geng, L., Maeda, Y., Nishimura, S., Witzgall, R., Ehrlich, B. E., Somlo, S. <strong>Polycystin-2 is an intracellular calcium release channel.</strong> Nature Cell Biol. 4: 191-197, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854751</a>] [<a href="https://doi.org/10.1038/ncb754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854751">Koulen et al. (2002)</a> investigated subcellular localization and calcium channel activity of PKD2 by overexpressing the full-length gene, a C-terminal truncated polycystin-2 mutant, and the asp511-to-val mutation (D522V; <a href="#0008">173910.0008</a>) in porcine kidney cells. They found that polycystin-2 localizes to the endoplasmic reticulum (ER) and behaves as a calcium-activated, high conductance channel that is permeable to divalent cations. The C-terminal truncated mutant had no significant channel activity and showed altered subcellular localization caused by loss of the essential ER retention signal. The D511V variant retained ER subcellular localization, normal protein interaction, and the regulatory domains of the wildtype protein, but had loss of channel activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854751" 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="Gonzalez-Perrett, S., Kim, K., Ibarra, C., Damiano, A. E., Zotta, E., Batelli, M., Harris, P. C., Reisin, I. L., Arnaout, M. A., Cantiello, H. F. <strong>Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca(2+)-permeable nonselective cation channel.</strong> Proc. Nat. Acad. Sci. 98: 1182-1187, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11252306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11252306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11252306[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.98.3.1182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11252306">Gonzalez-Perrett et al. (2001)</a> demonstrated that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states and a high perm-selectivity to calcium ions. This channel was inhibited by antipolycystin-2 antibody and the diuretic amiloride. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD. <a href="#11" class="mim-tip-reference" title="Grantham, J. J., Calvet, J. P. <strong>Polycystic kidney disease: in danger of being X-rated?</strong> Proc. Nat. Acad. Sci. 98: 790-792, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158545</a>] [<a href="https://doi.org/10.1073/pnas.98.3.790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158545">Grantham and Calvet (2001)</a> reviewed observations suggesting that the polycystins regulate cell proliferation. They stated that 'it seems more likely that the polycystins will be found to be involved in the abnormal regulation of tubular epithelial cell proliferation rather than the transepithelial transport of electrolytes and water.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11252306+11158545" 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 polyclonal antisera raised against polycystin-2, <a href="#43" class="mim-tip-reference" title="Scheffers, M. S., Le, H., van der Bent, P., Leonhard, W., Prins, F., Spruit, L., Breuning, M. H., de Heer, E., Peters, D. J. M. <strong>Distinct subcellular expression of endogenous polycystin-2 in the plasma membrane and Golgi apparatus of MDCK cells.</strong> Hum. Molec. Genet. 11: 59-67, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11772999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11772999</a>] [<a href="https://doi.org/10.1093/hmg/11.1.59" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11772999">Scheffers et al. (2002)</a> demonstrated distinct expression of the endogenous polycystin-2 in the Golgi apparatus and the plasma membrane of MDCK cells. In contrast, most of the heterologously expressed polycystin-2-EGFP fusion protein remained in the ER, substantially overlapping with the staining pattern of protein-disulfide isomerase (PDI; <a href="/entry/176790">176790</a>), a marker for the ER. In a small subset of cells, weak plasma membrane signals were observed by immunoelectron microscopy and Western blotting of subcellular fractions. The plasma membrane staining disappeared following extraction with a mild detergent, suggesting that polycystin-2 is not tightly bound to the insoluble cytoskeleton, nor to polycystin-1. The authors concluded that endogenous polycystin-2 is transported via the Golgi apparatus to the plasma membrane and has a broader membrane localization than polycystin-1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11772999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bhunia, A. K., Piontek, K., Boletta, A., Liu, L., Qian, F., Xu, P.-N., Germino, F. J., Germino, G. G. <strong>PKD1 induces p21-waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2.</strong> Cell 109: 157-168, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007403</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00716-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007403">Bhunia et al. (2002)</a> showed that expression of polycystin-1 activates the JAK (see <a href="/entry/147795">147795</a>)-STAT (see STAT1; <a href="/entry/600555">600555</a>) pathway, thereby upregulating WAF1 (CDKN1A; <a href="/entry/116899">116899</a>) and inducing cell cycle arrest in G0/G1. They found that this process requires polycystin-2 as an essential cofactor. Mutations that disrupted binding of polycystin-1 and -2 prevented activation of the pathway. Mouse embryos lacking Pkd1 had defective STAT1 phosphorylation and Waf1 induction. These results suggested that 1 function of the complex of polycystin-1 and -2 is to regulate the JAK-STAT pathway and explained how mutations of either gene can result in dysregulated growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007403" 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 coimmunoprecipitation and cosedimentation techniques, <a href="#33" class="mim-tip-reference" title="Newby, L. J., Streets, A. J., Zhao, Y., Harris, P. C., Ward, C. J., Ong, A. C. <strong>Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex.</strong> J. Biol. Chem. 277: 20763-20773, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11901144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11901144</a>] [<a href="https://doi.org/10.1074/jbc.M107788200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11901144">Newby et al. (2002)</a> found that 7 to 8% of polycystin-2 colocalizes with polycystin-1 in plasma membrane fractions of both normal human kidney and mouse kidney cells transgenic for human PKD1. Polycystin-2 is a glycoprotein with 5 putative N-glycosylation sites; it is endoglycosidase H (Endo H)-sensitive, indicating that the mature protein contains high mannose-type oligosaccharides. Polycystin-1 is heavily N-glycosylated and contains both Endo-H sensitive and mature Endo-H-resistant forms, both of which are able to interact with polycystin-2. <a href="#33" class="mim-tip-reference" title="Newby, L. J., Streets, A. J., Zhao, Y., Harris, P. C., Ward, C. J., Ong, A. C. <strong>Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex.</strong> J. Biol. Chem. 277: 20763-20773, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11901144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11901144</a>] [<a href="https://doi.org/10.1074/jbc.M107788200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11901144">Newby et al. (2002)</a> interpreted these results to suggest early association of the 2 proteins in the ER/cis-Golgi prior to insertion into the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11901144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Grimm, D. H., Cai, Y., Chauvet, V., Rajendran, V., Zeltner, R., Geng, L., Avner, E. D., Sweeney, W., Somlo, S., Caplan, M. J. <strong>Polycystin-1 distribution is modulated by polycystin-2 expression in mammalian cells.</strong> J. Biol. Chem. 278: 36786-36793, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840011</a>] [<a href="https://doi.org/10.1074/jbc.M306536200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840011">Grimm et al. (2003)</a> found that mammalian polycystin-1 localized to the cell surface and ER in cells that did not express polycystin-2. However, when the 2 proteins were coexpressed in the same cell line, polycystin-1 colocalized exclusively with polycystin-2 in the ER. Further work indicated that the subcellular localization of polycystin-1 depended on the ratio of polycystin-2 to polycystin-1 expression and that the localization of polycystin-1 could be regulated via the relative expression level of polycystin-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840011" 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="#28" class="mim-tip-reference" title="Luo, Y., Vassilev, P. M., Li, X., Kawanabe, Y., Zhou, J. <strong>Native polycystin 2 functions as a plasma membrane Ca(2+)-permeable cation channel in renal epithelia.</strong> Molec. Cell. Biol. 23: 2600-2607, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640140</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12640140[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.7.2600-2607.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640140">Luo et al. (2003)</a> found endogenous polycystin-2 expressed in the plasma membrane and the primary cilium of mouse inner medullar collecting duct cells and in canine kidney cells, whereas heterologously expressed polycystin-2 showed a predominant ER localization. Patch-clamping of inner medullar collecting duct cells expressing endogenous or heterologous polycystin-2 confirmed the presence of the channel on the plasma membrane. Treatment with chaperone-like factors facilitated the translocation of the polycystin-2 channel to the plasma membrane from intracellular pools. <a href="#28" class="mim-tip-reference" title="Luo, Y., Vassilev, P. M., Li, X., Kawanabe, Y., Zhou, J. <strong>Native polycystin 2 functions as a plasma membrane Ca(2+)-permeable cation channel in renal epithelia.</strong> Molec. Cell. Biol. 23: 2600-2607, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640140</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12640140[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.7.2600-2607.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640140">Luo et al. (2003)</a> concluded that polycystin-2 functions as a plasma membrane channel in renal epithelia and that it contributes to Ca(2+) entry and transport of other cations in defined nephron segments in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640140" 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 PKD1 and PKD2 proteins' interaction with each other through their C termini suggests that the 2 proteins are part of the same protein complex or signal transduction pathway. Using a yeast 2-hybrid screen with the PKD2 protein, <a href="#8" class="mim-tip-reference" title="Gallagher, A. R., Cedzich, A., Gretz, N., Somlo, S., Witzgall, R. <strong>The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton.</strong> Proc. Nat. Acad. Sci. 97: 4017-4022, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10760273[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.97.8.4017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10760273">Gallagher et al. (2000)</a> isolated the PKD2-interacting protein HAX1 (<a href="/entry/605998">605998</a>). Specificity of the interaction was demonstrated by the failure of PKD2L (<a href="/entry/604532">604532</a>), a protein closely related to PKD2, to interact with HAX1. Immunofluorescence experiments showed that in most cells PKD2 and HAX1 colocalized in the cell body, but in some cells they also were sorted into cellular processes and lamellipodia. <a href="#8" class="mim-tip-reference" title="Gallagher, A. R., Cedzich, A., Gretz, N., Somlo, S., Witzgall, R. <strong>The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton.</strong> Proc. Nat. Acad. Sci. 97: 4017-4022, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10760273[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.97.8.4017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10760273">Gallagher et al. (2000)</a> demonstrated an association between HAX1 and the F-actin-binding protein cortactin (<a href="/entry/164765">164765</a>), which suggested a link between PKD2 and the actin cytoskeleton. <a href="#8" class="mim-tip-reference" title="Gallagher, A. R., Cedzich, A., Gretz, N., Somlo, S., Witzgall, R. <strong>The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton.</strong> Proc. Nat. Acad. Sci. 97: 4017-4022, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10760273[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.97.8.4017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10760273">Gallagher et al. (2000)</a> speculated that PKD2 is involved in the formation of cell-matrix contacts, which are dysfunctional without a wildtype PKD2 protein, thus leading to cystic enlargement of tubular structures in the kidney, liver, and pancreas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10760273" 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="#32" class="mim-tip-reference" title="Nauli, S. M., Alenghat, F. J, Luo, Y., Williams, E., Vassilev, P., Li, X., Elia, A. E. H., Lu, W., Brown, E. M., Quinn, S. J., Ingber, D. E., Zhou, J. <strong>Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.</strong> Nature Genet. 33: 129-137, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514735</a>] [<a href="https://doi.org/10.1038/ng1076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514735">Nauli et al. (2003)</a> showed that polycystin-1 and polycystin-2 in mice codistribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lacked functional polycystin-1 formed cilia but did not increase Ca(2+) influx in response to physiologic fluid flow. Blocking antibodies directed against polycystin-2 similarly abolished the flow response in wildtype cells as did inhibitors of the ryanodine receptor (RYR1; <a href="/entry/180901">180901</a>), whereas inhibitors of G proteins, phospholipase C (see <a href="/entry/600220">600220</a>), and inositol 1,4,5-trisphosphate receptors had no effect. These data suggested that polycystin-1 and polycystin-2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of polycystin-1 or polycystin-2 may therefore lead to polycystic kidney disease owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis. <a href="#5" class="mim-tip-reference" title="Calvet, J. P. <strong>Ciliary signaling goes down the tubes.</strong> Nature Genet. 33: 113-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514736</a>] [<a href="https://doi.org/10.1038/ng1078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514736">Calvet (2003)</a> reproduced a scanning electron micrograph of the inside of a collecting-duct cyst from a human autosomal dominant polycystic kidney, showing a single intercalated cell surrounded by principal cells, each with 1 or several primary cilia. Although the cilia on these cells appeared normal, they were presumably functionally defective because of the mutation in the PKD1 or PKD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12514736+12514735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By yeast 2-hybrid analysis, <a href="#23" class="mim-tip-reference" title="Li, Q., Montalbetti, N., Shen, P. Y., Dai, X.-Q., Cheeseman, C. I., Karpinski, E., Wu, G., Cantiello, H. F., Chen, X.-Z. <strong>Alpha-actinin associates with polycystin-2 and regulates its channel activity.</strong> Hum. Molec. Genet. 14: 1587-1603, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15843396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15843396</a>] [<a href="https://doi.org/10.1093/hmg/ddi167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15843396">Li et al. (2005)</a> showed that both intracellular N and C termini of polycystin-2 associated with alpha-actinins (see <a href="/entry/102575">102575</a>), actin-binding, and actin-bundling proteins. In vivo interaction between endogenous polycystin-2 and alpha-actinins was demonstrated by coimmunoprecipitation in human, canine, and rodent cell lines. Immunofluorescence experiments showed that polycystin-2 and alpha-actinin were partially colocalized in canine epithelial kidney, murine inner medullary collecting duct cells and fibroblasts, and human syncytiotrophoblast vesicles. Alpha-actinin substantially stimulated the channel activity of reconstituted polycystin-2 in a lipid bilayer system. <a href="#23" class="mim-tip-reference" title="Li, Q., Montalbetti, N., Shen, P. Y., Dai, X.-Q., Cheeseman, C. I., Karpinski, E., Wu, G., Cantiello, H. F., Chen, X.-Z. <strong>Alpha-actinin associates with polycystin-2 and regulates its channel activity.</strong> Hum. Molec. Genet. 14: 1587-1603, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15843396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15843396</a>] [<a href="https://doi.org/10.1093/hmg/ddi167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15843396">Li et al. (2005)</a> hypothesized that physical and functional interactions between polycystin-2 and alpha-actinin may play an important role in abnormal cell adhesion, proliferation, and migration observed in ADPKD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15843396" 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="#24" class="mim-tip-reference" title="Li, X., Luo, Y., Starremans, P. G., McNamara, C. A., Pei, Y., Zhou, J. <strong>Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2.</strong> Nature Cell Biol. 7: 1202-1212, 2005. Note: Erratum: Nature Cell Biol. 8: 100 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311606</a>] [<a href="https://doi.org/10.1038/ncb1326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311606">Li et al. (2005)</a> found that polycystin-2 overexpression in human embryonic kidney cells led to reduced cell proliferation. They showed that polycystin-2 interacted directly with ID2 (<a href="/entry/600386">600386</a>) and modulated the cell cycle via the ID2-CDKN1A-CDK2 (<a href="/entry/116953">116953</a>) pathway. The ID2-polycystin-2 interaction caused sequestration of ID2 in the cytoplasm and required polycystin-1-dependent serine phosphorylation of polycystin-2. Kidney epithelial cells from a mouse model of PKD1 showed abnormalities in the cell cycle that could be reversed by RNA interference-mediated inhibition of Id2 mRNA expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311606" 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="Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S., Ehrlich, B. E. <strong>Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.</strong> Proc. Nat. Acad. Sci. 104: 6454-6459, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17404231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17404231</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17404231[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.0610324104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17404231">Anyatonwu et al. (2007)</a> stated that polycystin-2 interacts with several integral membrane proteins, including TRPC1 (<a href="/entry/602343">602343</a>) and InsP3R (ITPR1; <a href="/entry/147265">147265</a>). They found that mouse Pkd2 coimmunoprecipitated with the cardiac ryanodine receptor Ryr2 (<a href="/entry/180902">180902</a>) from mouse heart. Biochemical assays showed that the N terminus of Pkd2 bound Ryr2, whereas the C terminus only bound to Ryr2 in its open state. Lipid bilayer electrophysiologic experiments indicated that the C terminus of Pkd2 functionally inhibited Ryr2 channel activity in the presence of Ca(2+). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17404231" 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="Li, X., Magenheimer, B. S., Xia, S., Johnson, T., Wallace, D. P., Calvet, J. P., Li, R. <strong>A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease.</strong> Nature Med. 14: 863-868, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18552856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18552856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18552856[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/nm1783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18552856">Li et al. (2008)</a> showed that TNF-alpha (<a href="/entry/191160">191160</a>), which is found in cystic fluid of humans with ADPKD, disrupted the localization of polycystin-2 to the plasma membrane and primary cilia through the TNF-alpha-induced scaffold protein FIP2 (OPTN; <a href="/entry/602432">602432</a>). Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in cyst formation, and this effect was exacerbated in Pkd2 +/- kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2 +/- mice, and treatment of Pkd2 +/- mice with a TNF-alpha inhibitor prevented cyst formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18552856" 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 kinetic analysis of spontaneous channel currents of PC2, <a href="#59" class="mim-tip-reference" title="Zhang, P., Luo, Y., Chasan, B., Gonzalez-Perrett, S., Montalbetti, N., Timpanaro, G. A., del Rocio Cantero, M., Ramos, A. J., Goldmann, W. H., Zhou, J., Cantiello, H. F. <strong>The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1.</strong> Hum. Molec. Genet. 18: 1238-1251, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19193631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19193631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19193631[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/10.1093/hmg/ddp024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19193631">Zhang et al. (2009)</a> showed that 4 intrinsic, non-stochastic subconductance states, which followed a staircase behavior, were both pH and voltage dependent. Low pH inhibited PC2 currents in PC2 homomeric complexes, but failed to affect PC2 currents in PC2/TRPC1 heteromeric complexes. In contrast, amiloride abolished PC2 currents in both homomeric PC2 complexes and heteromeric PC2/TRPC1 complexes, indicating that PC2/TRPC1 complexes have distinct functional properties from the homomeric complexes. The topologic features of the homomeric PC2 and TRPC1 complexes and the heteromeric PC2/TRPC1 complex were consistent with structural tetramers. <a href="#59" class="mim-tip-reference" title="Zhang, P., Luo, Y., Chasan, B., Gonzalez-Perrett, S., Montalbetti, N., Timpanaro, G. A., del Rocio Cantero, M., Ramos, A. J., Goldmann, W. H., Zhou, J., Cantiello, H. F. <strong>The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1.</strong> Hum. Molec. Genet. 18: 1238-1251, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19193631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19193631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19193631[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/10.1093/hmg/ddp024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19193631">Zhang et al. (2009)</a> proposed tetrameric models for both the PC2 and TRPC1 channels, where the overall conductance of a particular channel depends on the contributions of the various functional monomers in the complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19193631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Liang, G., Li, Q., Tang, Y., Kokame, K., Kikuchi, T., Wu, G., Chen, X.-Z. <strong>Polycystin-2 is regulated by endoplasmic reticulum-associated degradation.</strong> Hum. Molec. Genet. 17: 1109-1119, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18178578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18178578</a>] [<a href="https://doi.org/10.1093/hmg/ddm383" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18178578">Liang et al. (2008)</a> showed that wildtype and C-terminally truncated mutants of PC2 that cause PKD2 were eliminated by ER-associated degradation (ERAD) via the ubiquitin-proteasome system. Both N- and C-terminal regions of PC2 interacted with HERP (HERPUD1; <a href="/entry/608070">608070</a>), and this interaction was required for PC2 degradation. PC2 lacking both N and C termini did not interact with HERP and was not degraded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18178578" 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>ER stress increases the kinase activity of PERK (EIF2AK3; <a href="/entry/604032">604032</a>) to promote EIF2-alpha (EIF2S1; <a href="/entry/603907">603907</a>) phosphorylation, which results in translational repression and reduced cell growth. Using several mammalian cell lines, including human cell lines, in overexpression and knockdown studies, <a href="#27" class="mim-tip-reference" title="Liang, G., Yang, J., Wang, Z., Li, Q., Tang, Y., Chen, X.-Z. <strong>Polycystin-2 down-regulates cell proliferation via promoting PERK-dependent phosphorylation of eIF2-alpha.</strong> Hum. Molec. Genet. 17: 3254-3262, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18664456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18664456</a>] [<a href="https://doi.org/10.1093/hmg/ddn221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18664456">Liang et al. (2008)</a> showed that PC2 downregulated cell proliferation through the PERK-EIF2-alpha signaling pathway. Coimmunoprecipitation experiments revealed that PC2 interacted in a complex with PERK and EIF2-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18664456" 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="#45" class="mim-tip-reference" title="Sharif-Naeini, R., Folgering, J. H. A., Bichet, D., Duprat, F., Lauritzen, I., Arhatte, M., Jodar, M., Dedman, A., Chatelain, F. C., Schulte, U., Retailleau, K., Loufrani, L., Patel, A., Sachs, F., Delmas, P., Peters, D. J. M., Honore, E. <strong>Polycystin-1 and -2 dosage regulates pressure sensing.</strong> Cell 139: 587-596, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19879844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19879844</a>] [<a href="https://doi.org/10.1016/j.cell.2009.08.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19879844">Sharif-Naeini et al. (2009)</a> showed that mouse Pkd1 and Pkd2, which they called Trpp1 and Trpp2, could regulate stretch-activated ion channels and were involved in pressure sensing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19879844" 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="#48" class="mim-tip-reference" title="Tran, U., Zakin, L., Schweickert, A., Agrawal, R., Doger, R., Blum, M., De Robertis, E. M., Wessely, O. <strong>The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity.</strong> Development 137: 1107-1116, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20215348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20215348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20215348[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/10.1242/dev.046045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20215348">Tran et al. (2010)</a> found that embryonic Bicc1 (<a href="/entry/614295">614295</a>) -/- mice developed severely polycystic kidneys on both sides, as well as liver and pancreatic cysts and defects in left-right patterning. Quantitative PCR showed progressive downregulated expression of Pkd2, but not Pkd1 or Pkhd1 (<a href="/entry/606702">606702</a>), between embryonic days 15.5 and 18.5 in Bicc1 -/- kidneys compared with wildtype kidneys. Pkd2 expression was also lower than normal in Bicc1 +/- mouse kidneys and following morpholino-mediated Bicc1 knockdown in Xenopus larvae. Examination of the 3-prime UTR of Pkd2 transcripts revealed a target site for the Mir17 (see <a href="/entry/609416">609416</a>) family of microRNAs. Mutation within the Mir17-binding site reversed Pkd2 downregulation following Bicc1 knockdown in Xenopus larvae. Furthermore, expression of Mir17 duplexes reduced expression of Pkd2 3-prime UTR reporter genes, whereas expression of Bicc1 increased Pkd2 expression. <a href="#48" class="mim-tip-reference" title="Tran, U., Zakin, L., Schweickert, A., Agrawal, R., Doger, R., Blum, M., De Robertis, E. M., Wessely, O. <strong>The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity.</strong> Development 137: 1107-1116, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20215348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20215348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20215348[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/10.1242/dev.046045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20215348">Tran et al. (2010)</a> concluded that BICC1 regulates PKD2 expression by countering the inhibitory effect of MIR17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20215348" 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="#58" class="mim-tip-reference" title="Yoshiba, S., Shiratori, H., Kuo, I. Y., Kawasumi, A., Shinohara, K., Nonaka, S., Asai, Y., Sasaki, G., Belo, J. A., Sasaki, H., Nakai, J., Dworniczak, B., Ehrlich, B. E., Pennekamp, P., Hamada, H. <strong>Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2.</strong> Science 338: 226-231, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22983710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22983710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22983710[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.1222538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22983710">Yoshiba et al. (2012)</a> reported that the calcium ion channel polycystin-2 is required specifically in the perinodal crown cells for the sensing of nodal flow. Examination of mutant forms of Pkd2 showed that the ciliary localization of Pkd2 is essential for correct left-right patterning. Whereas Kif3a (<a href="/entry/604683">604683</a>) mutant embryos, which lack all cilia, failed to respond to an artificial flow, restoration of primary cilia in crown cells rescued the response to the flow. <a href="#58" class="mim-tip-reference" title="Yoshiba, S., Shiratori, H., Kuo, I. Y., Kawasumi, A., Shinohara, K., Nonaka, S., Asai, Y., Sasaki, G., Belo, J. A., Sasaki, H., Nakai, J., Dworniczak, B., Ehrlich, B. E., Pennekamp, P., Hamada, H. <strong>Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2.</strong> Science 338: 226-231, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22983710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22983710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22983710[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.1222538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22983710">Yoshiba et al. (2012)</a> concluded that their results suggested that nodal flow is sensed in a manner dependent on Pkd2 by the cilia of crown cells located at the edge of the node. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22983710" 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 mutant mouse cells and embryos, <a href="#12" class="mim-tip-reference" title="Grimes, D. T., Keynton, J. L., Buenavista, M. T., Jin, X., Patel, S. H., Kyosuke, S., Vibert, J., Williams, D. J., Hamada, H., Hussain, R., Nauli, S. M., Norris, D. P. <strong>Genetic analysis reveals a hierarchy of interactions between polycystin-encoding genes and genes controlling cilia function during left-right determination.</strong> PLoS Genet. 12: e1006070, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27272319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27272319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27272319[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/10.1371/journal.pgen.1006070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27272319">Grimes et al. (2016)</a> found that Pkd1l1 (<a href="/entry/609721">609721</a>) and Pkd2 required the ciliary structure to function and that Pkd1l1 was at least partially involved in Pkd2 localization to cilia. Pkd2 elicited bilateral Nodal gene expression in the absence of Pkd1l1. <a href="#12" class="mim-tip-reference" title="Grimes, D. T., Keynton, J. L., Buenavista, M. T., Jin, X., Patel, S. H., Kyosuke, S., Vibert, J., Williams, D. J., Hamada, H., Hussain, R., Nauli, S. M., Norris, D. P. <strong>Genetic analysis reveals a hierarchy of interactions between polycystin-encoding genes and genes controlling cilia function during left-right determination.</strong> PLoS Genet. 12: e1006070, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27272319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27272319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27272319[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/10.1371/journal.pgen.1006070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27272319">Grimes et al. (2016)</a> hypothesized that PKD1L1 represses PKD2 in the node and that nodal flow relieves this repression on the left side only, activating PKD2 and initiating a signaling cascade that results in left-sided NODAL activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27272319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Hurd, T., Zhou, W., Jenkins, P., Liu, C.-J., Swaroop, A., Khanna, H., Martens, J., Hildebrandt, F., Margolis, B. <strong>The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development.</strong> Hum. Molec. Genet. 19: 4330-4344, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729296</a>] [<a href="https://doi.org/10.1093/hmg/ddq355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729296">Hurd et al. (2010)</a> observed that RP2 (<a href="/entry/300757">300757</a>) formed a calcium-sensitive complex with PKD2 in renal epithelia. Ablation of RP2 by short hairpin RNA (shRNA) promoted swelling of the cilia tip that could represent aberrant trafficking of PKD2 and other ciliary proteins. In addition to the observed physical interaction between RP2 and PKD2, dual morpholino-mediated knockdown of PKD2 and RP2 resulted in enhanced situs inversus, indicating that these 2 genes may regulate a common developmental process. The authors suggested that RP2 may be an important regulator of ciliary function through its association with PKD2, and provided evidence of a further link between retinal and renal cilia function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729296" 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="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> analyzed the PKD2 gene in affected individuals in 3 families with type-2 polycystic kidney disease (PKD2; <a href="/entry/613095">613095</a>). They used reverse-transcribed RNA and genomic DNA templates to generate PCR products for SSCP analysis and sequencing. Three nonsense mutations in the PKD2 gene were identified in affected individuals; see <a href="#0001">173910.0001</a>, <a href="#0002">173910.0002</a>, and <a href="#0003">173910.0003</a>. These mutations were not present in controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" 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="#51" class="mim-tip-reference" title="Viribay, M., Hayashi, T., Telleria, D., Mochizuki, T., Reynolds, D. M., Alonso, R., Lens, X. M., Moreno, F., Harris, P. C., Somlo, S., San Millan, J. L. <strong>Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene.</strong> Hum. Genet. 101: 229-234, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9402976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9402976</a>] [<a href="https://doi.org/10.1007/s004390050621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9402976">Viribay et al. (1997)</a> used heteroduplex and SSCP analyses in a systematic mutation screening of all 15 exons of the PKD2 gene in chromosome 4-linked ADPKD families, They identified and characterized 7 novel mutations, with a detection rate of approximately 90% in the populations studied. All of the mutations resulted in the premature stop of translation: 4 nonsense changes (e.g., <a href="#0005">173910.0005</a>) and 3 deletions. The deletions were all frameshifting, of 4 T nucleotides in 1 case and 1 G nucleotide in the other 2. All the mutations were unique and were distributed throughout the gene without evidence of clustering. Comparison of specific mutations with a clinical profile in these families showed no clear correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9402976" 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="#50" class="mim-tip-reference" title="Veldhuisen, B., Saris, J. J., de Haij, S., Hayashi, T., Reynolds, D. M., Mochizuki, T., Elles, R., Fossdal, R., Bogdanova, N., van Dijk, M. A., Coto, E., Ravine, D., Norby, S., Verellen-Dumoulin, C., Breuning, M. H., Somlo, S., Peters, D. J. M. <strong>A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2).</strong> Am. J. Hum. Genet. 61: 547-555, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326320</a>] [<a href="https://doi.org/10.1086/515497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326320">Veldhuisen et al. (1997)</a> systematically screened the PKD2 gene for mutations by SSCP analysis in 35 families with ADPKD and identified 20 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326320" 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="Pei, Y., He, N., Wang, K., Kasenda, M., Paterson, A. D., Chan, G., Liang, Y., Roscoe, J., Brissenden, J., Hefferton, D., Parfrey, P., Somlo, S., St. George-Hyslop, P. <strong>A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.</strong> J. Am. Soc. Nephrol. 9: 1853-1860, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9773786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9773786</a>] [<a href="https://doi.org/10.1681/ASN.V9101853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9773786">Pei et al. (1998)</a> screened for PKD2 mutations in 11 Canadian families with ADPKD. In 4 families, linkage to PKD2 had been documented; in the remaining 7 smaller families, one or more affected members had late-onset end-stage renal disease at age 70 or older, a feature suggesting PKD2. <a href="#34" class="mim-tip-reference" title="Parfrey, P. S. N., Bear, J. C., Morgan, J., Cramer, B. C., McManamon, P. J., Gault, M. H., Churchill, D., Singh, M., Hewitt, R., Somlo, S., Reeders, S. <strong>The diagnosis and prognosis of autosomal dominant polycystic kidney disease.</strong> New Eng. J. Med. 323: 1085-1090, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2215575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2215575</a>] [<a href="https://doi.org/10.1056/NEJM199010183231601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2215575">Parfrey et al. (1990)</a> and <a href="#41" class="mim-tip-reference" title="Ravine, D., Walker, R. G., Gibson, R. N., Forrest, S. M., Richards, R. I., Friend, K., Sheffield, L. J., Kincaid-Smith, P., Danks, D. M. <strong>Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease.</strong> Lancet 340: 1330-1333, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1360045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1360045</a>] [<a href="https://doi.org/10.1016/0140-6736(92)92503-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1360045">Ravine et al. (1992)</a> had found a mean age of onset of ESRD among affected members in PKD1-linked families to be 56 years; in contrast, the mean age of onset of ESRD among affected members in PKD2-linked families was 70 years. <a href="#35" class="mim-tip-reference" title="Pei, Y., He, N., Wang, K., Kasenda, M., Paterson, A. D., Chan, G., Liang, Y., Roscoe, J., Brissenden, J., Hefferton, D., Parfrey, P., Somlo, S., St. George-Hyslop, P. <strong>A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.</strong> J. Am. Soc. Nephrol. 9: 1853-1860, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9773786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9773786</a>] [<a href="https://doi.org/10.1681/ASN.V9101853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9773786">Pei et al. (1998)</a> found mutations in 8 of the 11 families, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In 3 unrelated families, insertion or deletion of an adenosine in a polyadenosine tract, (A)8 at nucleotides 2152-2159, was found in exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from 'slipped strand mispairing.' All the mutations, scattered between exons 1 and 11, were predicted to result in a truncated polycystin-2 that lacks both the calcium-binding EF-hand domain and the 2 cytoplasmic domains required for the interaction of polycystin-2 with polycystin-1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2215575+1360045+9773786" 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 both kidneys of a patient with PKD2, <a href="#19" class="mim-tip-reference" title="Koptides, M., Hadjimichael, C., Koupepidou, P., Pierides, A., Deltas, C. C. <strong>Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 8: 509-513, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949210</a>] [<a href="https://doi.org/10.1093/hmg/8.3.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949210">Koptides et al. (1999)</a> identified, for the first time, multiple novel somatic mutations within the PKD2 gene of epithelial cells. The family involved in this case had previously been shown to possess a 1-bp insertion (<a href="#0004">173910.0004</a>) as the germline mutation. In 7 (33%) of 21 cysts examined, the authors identified a different 1-bp insertion (<a href="#0007">173910.0007</a>) within the inherited wildtype allele. In 2 other cysts, a nonsense mutation and a splice site deletion had occurred in a PKD2 allele that could not be identified as the inherited wildtype or mutant. <a href="#19" class="mim-tip-reference" title="Koptides, M., Hadjimichael, C., Koupepidou, P., Pierides, A., Deltas, C. C. <strong>Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 8: 509-513, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949210</a>] [<a href="https://doi.org/10.1093/hmg/8.3.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949210">Koptides et al. (1999)</a> suggested that the autosomal dominant form of PKD2 occurs by a cellular recessive mechanism, supporting a 2-hit model for cyst formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Koptides, M., Mean, R., Demetriou, K., Pierides, A., Deltas, C. C. <strong>Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 9: 447-452, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655555</a>] [<a href="https://doi.org/10.1093/hmg/9.3.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655555">Koptides et al. (2000)</a> provided the first direct genetic evidence that polycystins 1 and 2 interact, perhaps as part of a larger complex. In cystic DNA from a kidney of a patient with autosomal dominant PKD1, the authors showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a transheterozygous state with mutations in both genes. The mutation in PKD1 was of germinal nature and the mutation in PKD2 was of somatic nature. The authors stated that to their knowledge there was no precedent to the transheterozygous model as a mechanism for human disease development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655555" 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="#52" class="mim-tip-reference" title="Watnick, T., He, N., Wang, K., Liang, Y., Parfrey, P., Hefferton, D., St. George-Hyslop, P., Germino, G., Pei, Y. <strong>Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations.</strong> Nature Genet. 25: 143-144, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835625</a>] [<a href="https://doi.org/10.1038/75981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835625">Watnick et al. (2000)</a> found somatic mutations of PKD2 in 71% of ADPKD2 cysts analyzed. They found clonal somatic mutations of PKD1 in a subset of cysts that lacked PKD2 mutations. In 10 cysts, they demonstrated that the wildtype PKD2 allele had acquired the mutation. They found 3 PKD2 cysts with somatic PKD1 mutations in each cyst; comprehensive screening of the entire PKD2 coding sequence was negative. They referred to this as a pathogenic effect of transheterozygous mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835625" 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="#47" class="mim-tip-reference" title="Torra, R., Badenas, C., San Millan, J. L., Perez-Oller, L., Estivill, X., Darnell, A. <strong>A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.</strong> Am. J. Hum. Genet. 65: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417277</a>] [<a href="https://doi.org/10.1086/302501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417277">Torra et al. (1999)</a> sought to demonstrate that somatic mutations are present in renal cysts from a PKD2 kidney. They studied 30 renal cysts from a patient with PKD2 in whom the germline mutation was shown to be a deletion that encompassed most of the gene. Loss of heterozygosity (LOH) studies showed loss of a wildtype allele in 10% of cysts. Screening of 6 exons of the gene by SSCP detected 8 different somatic mutations, all of which were expected to produce truncated proteins. Overall, more than 37% of the cysts studied represented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 on chromosome 3 was observed in those cysts, which demonstrated that somatic alterations were specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10417277" 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="Pei, Y., Paterson, A. D., Wang, K. R., He, N., Hefferton, D., Watnick, T., Germino, G. G., Parfrey, P., Somlo, S., St. George-Hyslop, P. <strong>Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease.</strong> Am. J. Hum. Genet. 68: 355-363, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11156533[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11156533">Pei et al. (2001)</a> reported studies of an extensively affected Newfoundland family in which it appeared that there was bilineal disease from independently segregating PKD1 and PKD2 mutations. A PKD2 mutation (2152delA; L736X) was found in 12 affected pedigree members. In addition, when the disease status of these individuals was coded as unknown in linkage analysis, they found, with markers at the PKD1 locus, significant lod scores, i.e., greater than 3.0. The findings strongly supported the presence of a PKD1 mutation in 15 other affected pedigree members, who lacked the PKD2 mutation. Two additional affected individuals had transheterozygous mutations involving both genes, and they had renal disease that was more severe than that in affected individuals who had either mutation alone. This was said to be the first demonstration of bilineal disease in ADPKD. In humans, transheterozygous mutations involving both PKD1 and PKD2 are not necessarily embryonically lethal. The authors concluded that the presence of bilineal disease as a confounder needs to be considered in the search for the PKD3 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 2 unrelated families with polycystic kidney disease, <a href="#2" class="mim-tip-reference" title="Bataille, S., Demoulin, N., Devuyst, O., Audrezet, M.-P., Dahan, K., Godin, M., Fontes, M., Pirson, Y., Burtey, S. <strong>Association of PKD2 (polycystin 2) mutations with left-right laterality defects.</strong> Am. J. Kidney Dis. 58: 456-460, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719175</a>] [<a href="https://doi.org/10.1053/j.ajkd.2011.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719175">Bataille et al. (2011)</a> identified 2 different heterozygous mutations in the PKD2 gene (<a href="#0010">173910.0010</a> and <a href="#0011">173910.0011</a>). In addition to kidney disease, the proband from each of the families also showed laterality defects, including situs inversus and dextrocardia, that were not seen in other affected family members. A third proband with PKD2 and a large 80-kb deletion involving PKD2 and ABCG2 (<a href="/entry/603756">603756</a>) also had laterality defects. The findings suggested that laterality defects may occur in some patients with PKD2 mutations, as has been demonstrated in animal models (see, e.g., <a href="#38" class="mim-tip-reference" title="Pennekamp, P., Karcher, C., Fischer, A., Schweickert, A., Skryabin, B., Horst, J., Blum, M., Dworniczak, B. <strong>The ion channel polycystin-2 is required for left-right axis determination in mice.</strong> Curr. Biol. 12: 938-943, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062060</a>] [<a href="https://doi.org/10.1016/s0960-9822(02)00869-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062060">Pennekamp et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12062060+21719175" 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="#55" class="mim-tip-reference" title="Wu, G., Mochizuki, T., Le, T. C., Cai, Y., Hayashi, T., Reynolds, D. M., Somlo, S. <strong>Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2.</strong> Genomics 45: 220-223, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9339380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9339380</a>] [<a href="https://doi.org/10.1006/geno.1997.4920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9339380">Wu et al. (1997)</a> cloned the murine homolog, Pkd2, and mapped it to mouse chromosome 5. The map location excluded it as a candidate gene for previously mapped mouse mutations resulting in a polycystic kidney phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9339380" 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="#53" class="mim-tip-reference" title="Wu, G., D'Agati, V., Cai, Y., Markowitz, G., Park, J. H., Reynolds, D. M., Maeda, Y., Le, T. C., Hou, H., Jr., Kucherlapati, R., Edelmann, W., Somlo, S. <strong>Somatic inactivation of Pkd2 results in polycystic kidney disease.</strong> Cell 93: 177-188, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9568711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9568711</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81570-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9568711">Wu et al. (1998)</a> introduced a mutant exon 1 in tandem with the wildtype exon 1 at the mouse Pkd2 locus. This was an unstable allele that underwent somatic inactivation by intragenic homologous recombination to produce a true null Pkd2 allele. Mice heterozygous and homozygous for this mutation develop polycystic kidney and liver lesions that are indistinguishable from the human phenotype. In all cases, renal cysts arise from renal tubular cells that lose the capacity to produce Pkd2 protein. <a href="#53" class="mim-tip-reference" title="Wu, G., D'Agati, V., Cai, Y., Markowitz, G., Park, J. H., Reynolds, D. M., Maeda, Y., Le, T. C., Hou, H., Jr., Kucherlapati, R., Edelmann, W., Somlo, S. <strong>Somatic inactivation of Pkd2 results in polycystic kidney disease.</strong> Cell 93: 177-188, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9568711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9568711</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81570-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9568711">Wu et al. (1998)</a> concluded that somatic loss of Pkd2 expression is both necessary and sufficient for renal cyst formation in ADPKD, suggesting that PKD2 occurs by a cellular recessive mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9568711" 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="#54" class="mim-tip-reference" title="Wu, G., Markowitz, G. S., Li, L., D'Agati, V. D., Factor, S. M., Geng, L., Tibara, S., Tuchman, J., Cai, Y., Park, J. H., van Adelsberg, J., Hou, H., Jr., Kucherlapati, R., Edelmann, W., Somlo, S. <strong>Cardiac defects and renal failure in mice with targeted mutations in Pkd2.</strong> Nature Genet. 24: 75-78, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615132</a>] [<a href="https://doi.org/10.1038/71724" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10615132">Wu et al. (2000)</a> induced 2 mutations in the mouse homolog Pkd2: an unstable allele that can undergo homologous recombination-based somatic rearrangement to form a null allele; and a true null allele. They examined these mutations to understand the function of polycystin-2 and to provide evidence that kidney and liver cyst formation associated with Pkd2 deficiency occurs by a 2-hit mechanism. They found that Pkd2 -/- mice die in utero between embryonic day (E) 13.5 and parturition. They have structural defects in cardiac septation and cyst formation in maturing nephrons and pancreatic ducts. Pancreatic ductal cysts also occur in adult Pkd2 mice heterozygous for the unstable allele, suggesting that this clinical manifestation of ADPKD also occurs by a 2-hit mechanism. As in human ADPKD, formation of kidney cysts in adult mice heterozygous for the unstable allele is associated with renal failure and early death (median survival, 65 weeks vs 94 weeks for controls). Adult mice heterozygous for the null mutation have intermediate survival despite absence of cystic disease or renal failure, providing the first indication of a deleterious effect of haploinsufficiency at Pkd2 on long-term survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10615132" 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="#56" class="mim-tip-reference" title="Wu, G., Tian, X., Nishimura, S., Markowitz, G. S., D'Agati, V., Park, J. H., Yao, L., Li, L., Geng, L., Zhao, H., Edelmann, W., Somlo, S. <strong>Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease.</strong> Hum. Molec. Genet. 11: 1845-1854, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140187</a>] [<a href="https://doi.org/10.1093/hmg/11.16.1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140187">Wu et al. (2002)</a> investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1 +/-, Pkd2 +/-, and Pkd1 +/- : Pkd2 +/- mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the 2-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 +/- mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1 +/- : Pkd2 +/- mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. These data suggested a modifier role for the 'trans' polycystin gene in cystic kidney disease, and supported a contribution from threshold effects to cyst formation and growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140187" 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 mouse embryos, <a href="#38" class="mim-tip-reference" title="Pennekamp, P., Karcher, C., Fischer, A., Schweickert, A., Skryabin, B., Horst, J., Blum, M., Dworniczak, B. <strong>The ion channel polycystin-2 is required for left-right axis determination in mice.</strong> Curr. Biol. 12: 938-943, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062060</a>] [<a href="https://doi.org/10.1016/s0960-9822(02)00869-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062060">Pennekamp et al. (2002)</a> found ubiquitous expression of the Pkd2 gene from the 2-cell to the compact blastocyst stage. It was also expressed at the headfold and early somite stages, with higher levels in the floorplate and notocord. Knockout of Pkd2 was embryonic lethal between days E12.5 and birth, and the mutant embryos showed multiple laterality defects. Heterozygous Pkd2 +/- mice also showed laterality defects, including right pulmonary isomerism, randomization of embryonic turning, heart looping, and abdominal situs. There was also lack of expression of Leftb (<a href="/entry/603037">603037</a>) and Nodal (<a href="/entry/601265">601265</a>) in the left lateral mesoderm plate, absence of Ebaf (<a href="/entry/601877">601877</a>) at the floorplate, and lack of Pitx2 (<a href="/entry/601542">601542</a>) in the left lateral mesoderm anteriorly; all of these genes are involved in the left-right signaling pathway. However, the embryonic midline was present and there were normal levels of Shh (<a href="/entry/600725">600725</a>). The findings suggested that Pkd2 acts in parallel with or downstream of Shh and upstream of the Nodal cascade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12062060" 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="Qian, Q., Hunter, L. W., Li, M., Marin-Padilla, M., Prakash, Y. S., Somlo, S., Harris, P. C., Torres, V. E., Sieck, G. C. <strong>Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells.</strong> Hum. Molec. Genet. 12: 1875-1880, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874107</a>] [<a href="https://doi.org/10.1093/hmg/ddg190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12874107">Qian et al. (2003)</a> found that the level of polycystin-2 expression in mouse Pkd2 +/- vessels was roughly half that of wildtype and that the level of intracranial vascular abnormalities in Pkd2 +/- mice was enhanced when induced to develop hypertension by unilateral carotid ligation. In addition, Pkd2 +/- vascular smooth muscle cells had significantly altered intracellular calcium homeostasis. The resting intracellular calcium concentration was lower in Pkd2 +/- compared with wildtype cells (p = 0.0003) and the total sarcoplasmic reticulum calcium store was decreased (p less than 0.0001). The store-operated calcium (SOC) channel activity was also decreased in Pkd2 +/- cells (p = 0.008). These results indicated that inactivation of just 1 Pkd2 allele is sufficient to alter significantly intracellular calcium homeostasis and that polycystin-2 may be necessary to maintain normal SOC activity and the sarcoplasmic reticulum calcium store in vascular smooth muscle cells. <a href="#40" class="mim-tip-reference" title="Qian, Q., Hunter, L. W., Li, M., Marin-Padilla, M., Prakash, Y. S., Somlo, S., Harris, P. C., Torres, V. E., Sieck, G. C. <strong>Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells.</strong> Hum. Molec. Genet. 12: 1875-1880, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874107</a>] [<a href="https://doi.org/10.1093/hmg/ddg190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12874107">Qian et al. (2003)</a> concluded that the abnormal intracellular calcium regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12874107" 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 embryonic mice, <a href="#30" class="mim-tip-reference" title="McGrath, J., Somlo, S., Makova, S., Tian, X., Brueckner, M. <strong>Two populations of node monocilia initiate left-right asymmetry in the mouse.</strong> Cell 114: 61-73, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12859898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12859898</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00511-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12859898">McGrath et al. (2003)</a> found expression of the Pkd2 gene in 2 types of cilia at the embryonic node around days E7.0-E8.0 during the period of leftward, ciliary-driven nodal flow that is important in left-right patterning. There appeared to be 2 sets of monocilia at the node: centrally located, motile monocilia containing Pkd2 and the axonemal dynein Dnahc11 (<a href="/entry/603339">603339</a>), and peripherally located, immotile monocilia containing only Pkd2. Around the time of embryonic nodal flow, there was an asymmetric distribution of intracellular calcium prominent in cells at the left margin of the node, but not at the right margin. Dnahc11-null embryos showed abnormalities in this asymmetric calcium signaling at the node, either left, bilateral, or absent, suggesting randomization. Pkd2-null embryos showed a complete lack of calcium signaling, suggesting that Pkd2 functions as a mechanotransducer of leftward flow into increased calcium signaling. The findings indicated that the 2 types of ciliary proteins coordinate to determine proper left-right signaling in the mouse embryo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12859898" 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="Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S., Ehrlich, B. E. <strong>Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.</strong> Proc. Nat. Acad. Sci. 104: 6454-6459, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17404231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17404231</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17404231[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.0610324104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17404231">Anyatonwu et al. (2007)</a> stated that Pkd2-null mice develop cardiovascular abnormalities. They found that cardiomyocytes cultured from mouse embryos lacking Pkd2 exhibited a significantly higher frequency of spontaneous oscillations compared with cells from wildtype embryos, presumably due to relief of Ryr2 (<a href="/entry/180902">180902</a>) inhibition. In addition, Pkd2-null cardiomyocytes had reduced levels of Ca(2+) in the sarcoplasmic reticulum and subsequently showed reduced amplitude for the Ca(2+) transients compared with wildtype cardiomyocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17404231" 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="Gao, H., Wang, Y., Wegierski, T., Skouloudaki, K., Putz, M., Fu, X., Engel, C., Boehlke, C., Peng, H., Kuehn, E. W., Kim, E., Kramer-Zucker, A., Walz, G. <strong>PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation.</strong> Hum. Molec. Genet. 19: 16-24, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801576</a>] [<a href="https://doi.org/10.1093/hmg/ddp463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19801576">Gao et al. (2010)</a> showed that overexpression or depletion of Prkcsh in zebrafish embryos led to pronephric cysts, abnormal body curvature, and situs inversus. Identical phenotypic changes were induced by depletion or overexpression of Pkd2. Increased Prkcsh levels ameliorated developmental abnormalities caused by overexpressed Pk2, whereas excess Pkd2 could compensate the loss of Prkcsh, indicating that the proteins may share a common signaling pathway. Prkcsh bound the C-terminal domain of Pkd2, and both proteins colocalized within the ER. Furthermore, Prkcsh interacted with Herp (HERPUD1; <a href="/entry/608070">608070</a>), and inhibited Herp-mediated ubiquitination of Pkd2. <a href="#9" class="mim-tip-reference" title="Gao, H., Wang, Y., Wegierski, T., Skouloudaki, K., Putz, M., Fu, X., Engel, C., Boehlke, C., Peng, H., Kuehn, E. W., Kim, E., Kramer-Zucker, A., Walz, G. <strong>PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation.</strong> Hum. Molec. Genet. 19: 16-24, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801576</a>] [<a href="https://doi.org/10.1093/hmg/ddp463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19801576">Gao et al. (2010)</a> suggested that PRKCSH may function as a chaperone-like molecule, which may prevent ERAD of PKD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19801576" 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 a combination of targeted knockout and overexpression with 2 genes mutated in polycystic liver disease (PCLD; <a href="/entry/174050">174050</a>), Prkcsh (<a href="/entry/177060">177060</a>) and Sec63 (<a href="/entry/608648">608648</a>), and 3 genes mutated in polycystic kidney disease, Pkd1, Pkd2, and Pkhd1, <a href="#6" class="mim-tip-reference" title="Fedeles, S. V., Tian, X., Gallagher, A.-R., Mitobe, M., Nishio, S., Lee, S. H., Cai, Y., Geng, L., Crews, C. M., Somlo, S. <strong>A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.</strong> Nature Genet. 43: 639-647, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21685914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21685914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21685914[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.860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21685914">Fedeles et al. (2011)</a> produced a spectrum of cystic disease severity in mice. Cyst formation in all combinations of these genes, except complete loss of Pkd2, was significantly modulated by altering expression of Pkd1. Proteasome inhibition increased the steady-state levels of Pkd1 in cells lacking Prkcsh and reduced cystic disease in mouse models of autosomal dominant polycystic liver disease. <a href="#6" class="mim-tip-reference" title="Fedeles, S. V., Tian, X., Gallagher, A.-R., Mitobe, M., Nishio, S., Lee, S. H., Cai, Y., Geng, L., Crews, C. M., Somlo, S. <strong>A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.</strong> Nature Genet. 43: 639-647, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21685914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21685914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21685914[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.860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21685914">Fedeles et al. (2011)</a> concluded that PRKCSH, SEC63, PKD1, PKD2, and PKHD1 form an interaction network with PKD1 as the rate-limiting component. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21685914" 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="Kamura, K., Kobayashi, D., Uehara, Y., Koshida, S., Iijima, N., Kudo, A., Yokoyama, T., Takeda, H. <strong>Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left-right axis.</strong> Development 138: 1121-1129, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307098</a>] [<a href="https://doi.org/10.1242/dev.058271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307098">Kamura et al. (2011)</a> and <a href="#7" class="mim-tip-reference" title="Field, S., Riley, K.-L., Grimes, D. T., Hilton, H., Simon, M., Powles-Glover, N., Siggers, P., Bogani, D., Greenfield, A., Norris, D. P. <strong>Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2.</strong> Development 138: 1131-1142, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307093</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307093[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/10.1242/dev.058149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307093">Field et al. (2011)</a> independently studied mutant medaka fish and mouse embryos, respectively, and found that Pkd2 functionally interacted with Pkd1l1 at nodal cilia. Both proteins were required for normal left-right patterning and gene expression during embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21307098+21307093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Khonsari, R. H., Ohazama, A., Raouf, R., Kawasaki, M., Kawasaki, K., Porntaveetus, T., Ghafoor, S., Hammond, P., Suttie, M., Odri, G. A., Sandford, R. N., Wood, J. N., Sharpe, P. T. <strong>Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2).</strong> Hum. Molec. Genet. 22: 1873-1885, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23390131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23390131</a>] [<a href="https://doi.org/10.1093/hmg/ddt041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23390131">Khonsari et al. (2013)</a> found that mice with conditional deletion of the Pkd2 gene in neural crest-derived cells showed signs of mechanical trauma to craniofacial structures, such as fractured molar roots, distorted incisors, alveolar bone loss, and compressed temporomandibular joints, as well as abnormal skull shapes. The phenotype was not apparent during embryonic stages, suggesting that postnatal mechanical stress is important for the development of these structures. Pkd2 was expressed ubiquitously in craniofacial structures during embryonic stages, but showed more restricted tissue expression after birth. In addition, several aneurysms and enlarged ventricles were found in mutant mouse brains. Three-dimensional photographic analysis of the craniofacial features of 19 human PKD2 patients showed some specific characteristics, including increased facial asymmetry, vertical lengthening of the face and nose, and mild mid-facial hypoplasia. The results suggested that the PKD2 gene plays a role in craniofacial growth as a mechanoreceptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23390131" 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="#29" class="mim-tip-reference" title="Ma, M., Tian, X., Igarashi, P., Pazour, G. J., Somlo, S. <strong>Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.</strong> Nature Genet. 45: 1004-1012, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23892607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23892607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23892607[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.2715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23892607">Ma et al. (2013)</a> noted that, like loss of either Pkd1 or Pkd2, loss of cilia following ablation of intraflagellar transport results in cyst formation in animal models. <a href="#29" class="mim-tip-reference" title="Ma, M., Tian, X., Igarashi, P., Pazour, G. J., Somlo, S. <strong>Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.</strong> Nature Genet. 45: 1004-1012, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23892607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23892607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23892607[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.2715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23892607">Ma et al. (2013)</a> combined conditional inactivation of Pkd1 or Pkd2 in mice with conditional inactivation of the intraflagellar transport genes Kif3a and Ift20 (<a href="/entry/614394">614394</a>). They found that structurally intact cilia were required to promote cyst growth following loss of Pkd1 or Pkd2. In contrast, Pkd1 or Pkd2 were not required for cyst development following loss of intraflagellar transport. Furthermore, combined loss of cilia and Pkd1 or Pkd2 significantly slowed cell growth and cyst formation in all mouse nephron segments and in liver. <a href="#29" class="mim-tip-reference" title="Ma, M., Tian, X., Igarashi, P., Pazour, G. J., Somlo, S. <strong>Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.</strong> Nature Genet. 45: 1004-1012, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23892607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23892607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23892607[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.2715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23892607">Ma et al. (2013)</a> concluded that PKD1 and PKD2 inhibit a cilia-dependent proliferative pathway that results in cyst formation. This signaling pathway appeared to be independent of signaling through MAPK/ERK, MTOR (<a href="/entry/601231">601231</a>), or cAMP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23892607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a family (family 97) with chromosome 4-linked polycystic kidney disease-2 (PKD2; <a href="/entry/613095">613095</a>), <a href="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> identified a G-to-A transition in the PKD2 gene that resulted in a change at codon 380 from trp to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" 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> rs121918040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918040;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/rs121918040?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=rs121918040" 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=rs121918040" 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=RCV000014473 OR RCV000518276 OR RCV000654888" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014473, RCV000518276, RCV000654888" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014473...</a>
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<p>In affected members of a Cypriot family (family 1605) with chromosome 4-linked polycystic kidney disease-2 (PKD2; <a href="/entry/613095">613095</a>), <a href="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> identified a C-to-T transition in the PKD2 gene that resulted in a change at codon 740 from arg to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" 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">rs121918041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918041;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=rs121918041" 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=rs121918041" 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=RCV000014474" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014474" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014474</a>
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<p>In a second unrelated Cypriot family (family 1601) with chromosome 4-linked polycystic kidney disease-2 (PKD2; <a href="/entry/613095">613095</a>), <a href="#31" class="mim-tip-reference" title="Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S. L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Constantinou Deltas, C., Peters, D. J. M., Somlo, S. <strong>PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.</strong> Science 272: 1339-1342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650545</a>] [<a href="https://doi.org/10.1126/science.272.5266.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650545">Mochizuki et al. (1996)</a> identified a C-to-T transition in the PKD2 gene that resulted in a change at codon 405 from gln to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 POLYCYSTIC KIDNEY DISEASE 2</strong>
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PKD2, 1-BP INS, 693C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1560598042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560598042;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=rs1560598042" 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=rs1560598042" 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=RCV000014475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014475</a>
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<p>By systematically screening the entire coding sequence of the PKD2 gene by SSCP analysis and heteroduplex formation in a Cypriot family with polycystic kidney disease (PKD2; <a href="/entry/613095">613095</a>), <a href="#57" class="mim-tip-reference" title="Xenophontos, S., Constantinides, R., Hayashi, T., Mochizuki, T., Somlo, S., Pierides, A., Constantinou Deltas, C. <strong>A transition frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PKD2).</strong> Hum. Molec. Genet. 6: 949-952, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9175744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9175744</a>] [<a href="https://doi.org/10.1093/hmg/6.6.949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9175744">Xenophontos et al. (1997)</a> identified insertion of a cytosine in exon 2 immediately after codon 231. It caused a translation frameshift and was expected to lead to the introduction of 37 novel amino acids before the translation reached a new stop codon. This was the most N-terminal mutation reported to that time, and based on the protein's modeled structure, it was predicted to be within the first transmembrane domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9175744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 POLYCYSTIC KIDNEY DISEASE 2</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">rs121918042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918042;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=rs121918042" 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=rs121918042" 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=RCV000014476 OR RCV001292355 OR RCV001659695 OR RCV003764572" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014476, RCV001292355, RCV001659695, RCV003764572" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014476...</a>
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<p><a href="#51" class="mim-tip-reference" title="Viribay, M., Hayashi, T., Telleria, D., Mochizuki, T., Reynolds, D. M., Alonso, R., Lens, X. M., Moreno, F., Harris, P. C., Somlo, S., San Millan, J. L. <strong>Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene.</strong> Hum. Genet. 101: 229-234, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9402976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9402976</a>] [<a href="https://doi.org/10.1007/s004390050621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9402976">Viribay et al. (1997)</a> identified 7 novel mutations in the PKD2 gene in patients with polycystic kidney disease (PKD2; <a href="/entry/613095">613095</a>), including a C-to-T transition at nucleotide 1456 in exon 6, resulting in an arg464-to-ter substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9402976" 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> rs757757289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs757757289;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/rs757757289?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=rs757757289" 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=rs757757289" 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=RCV000014477 OR RCV001254204 OR RCV001292200 OR RCV001559801 OR RCV002513045 OR RCV004752706" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014477, RCV001254204, RCV001292200, RCV001559801, RCV002513045, RCV004752706" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014477...</a>
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<p><a href="#37" class="mim-tip-reference" title="Pei, Y., Wang, K., Kasenda, M., Paterson, A. D., Liang, Y., Huang, E., Lian, J., Rogovea, E., Somlo, S., St. George-Hyslop, P. <strong>A novel frameshift mutation induced by an adenosine insertion in the polycystic kidney disease 2 (PKD2) gene.</strong> Kidney Int. 53: 1127-1132, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9573526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9573526</a>] [<a href="https://doi.org/10.1046/j.1523-1755.1998.00890.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9573526">Pei et al. (1998)</a> identified a novel mutation in the PKD2 gene in a large 4-generation family in which they had mapped polycystic kidney disease to chromosome 4 (PKD2; <a href="/entry/613095">613095</a>). The mutation was a single adenosine insertion in the polyadenosine tract (nucleotides 2152-2159) of exon 11 and was predicted to result in a frameshift with premature translation termination of the PKD product, polycystin-2, immediately after codon 723. The truncated polycystin-2 was predicted to lack the calcium-binding EF-hand domain and 2 cytoplasmic domains required for the homodimerization of polycystin-2 with itself and for the heterodimerization of polycystin-2 with polycystin-1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9573526" 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">rs1187336837 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1187336837;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=rs1187336837" 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=rs1187336837" 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=RCV000555382 OR RCV000681716 OR RCV002289770 OR RCV004752949 OR RCV004955664" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000555382, RCV000681716, RCV002289770, RCV004752949, RCV004955664" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000555382...</a>
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<p>In 7 of 21 cysts from both kidneys of a patient with polycystic kidney disease (PKD2; <a href="/entry/613095">613095</a>), <a href="#19" class="mim-tip-reference" title="Koptides, M., Hadjimichael, C., Koupepidou, P., Pierides, A., Deltas, C. C. <strong>Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 8: 509-513, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949210</a>] [<a href="https://doi.org/10.1093/hmg/8.3.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949210">Koptides et al. (1999)</a> identified a C insertion within the inherited wildtype PKD2 allele. This C insertion was different from the one previously identified (693insC; <a href="#0004">173910.0004</a>) in this family as the germline mutation. The insertion occurred within a sequence of 6 consecutive cytosines (nucleotides 197-203), encoding amino acids 66-68. The authors were unable to determine exactly where the insertion of the cytosine occurred. The mutation was expected to create a translation frameshift, leading to the incorporation of 22 novel amino acids before reaching a stop codon. A polymorphism at nucleotide 83, which was occupied by either G or C, encoding either arginine or proline, enabled <a href="#19" class="mim-tip-reference" title="Koptides, M., Hadjimichael, C., Koupepidou, P., Pierides, A., Deltas, C. C. <strong>Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 8: 509-513, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949210</a>] [<a href="https://doi.org/10.1093/hmg/8.3.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949210">Koptides et al. (1999)</a> to verify that the C insertion had occurred in the inherited wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 POLYCYSTIC KIDNEY DISEASE 2</strong>
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PKD2, ASP511VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918043;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=rs121918043" 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=rs121918043" 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=RCV000014479" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014479" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014479</a>
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<p>In affected members of a family with polycystic kidney disease (PKD2; <a href="/entry/613095">613095</a>), <a href="#42" class="mim-tip-reference" title="Reynolds, D. M., Hayashi, T., Cai, Y., Veldhuisen, B., Watnick, T. J., Lens, X. M., Mochizuki, T., Qian, F., Maeda, Y., Li, L., Fossdal, R., Coto, E., Wu, G., Breuning, M. H., Germino, G. G., Peters, D. J. M., Somlo, S. <strong>Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease.</strong> J. Am. Soc. Nephrol. 10: 2342-2351, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10541293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10541293</a>] [<a href="https://doi.org/10.1681/ASN.V10112342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10541293">Reynolds et al. (1999)</a> identified a 1532A-T transversion in the PKD2 gene, resulting in an asp511-to-val (D511V) substitution in the predicted third transmembrane span of polycystin-2. The loss-of-function mutation demonstrated complete segregation with the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10541293" 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 POLYCYSTIC KIDNEY DISEASE 2</strong>
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PKD2, 2-BP DEL/1-BP INS, NT1934
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1560621750 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560621750;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=rs1560621750" 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=rs1560621750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014480" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014480" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014480</a>
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<p>In affected members of a 4-generation family with polycystic kidney disease (PKD2; <a href="/entry/613095">613095</a>) that was clinically asymptomatic in the adults of the first 3 generations but manifested with perinatal death in the fourth generation, <a href="#3" class="mim-tip-reference" title="Bergmann, C., Bruchle, N. O., Frank, V., Rehder, H., Zerres, K. <strong>Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation. (Letter)</strong> New Eng. J. Med. 359: 318-319, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18635443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18635443</a>] [<a href="https://doi.org/10.1056/NEJMc0801868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18635443">Bergmann et al. (2008)</a> identified heterozygosity for a 2-bp deletion and 1-bp insertion (1934delACinsT) in exon 9 of the PKD2 gene, resulting in a frameshift predicted to cause premature termination. The mutation was not found in unaffected family members or in 200 ethnically matched control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18635443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<strong>.0010 POLYCYSTIC KIDNEY DISEASE 2</strong>
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PKD2, EX3DUP
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033172" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033172" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033172</a>
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<p>In a 64-year-old woman with polycystic kidney disease-2 (PKD2; <a href="/entry/613095">613095</a>), <a href="#2" class="mim-tip-reference" title="Bataille, S., Demoulin, N., Devuyst, O., Audrezet, M.-P., Dahan, K., Godin, M., Fontes, M., Pirson, Y., Burtey, S. <strong>Association of PKD2 (polycystin 2) mutations with left-right laterality defects.</strong> Am. J. Kidney Dis. 58: 456-460, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719175</a>] [<a href="https://doi.org/10.1053/j.ajkd.2011.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719175">Bataille et al. (2011)</a> identified a heterozygous duplication of exon 3 and the exon 3/intron boundary of the PKD2 gene, predicted to result in haploinsufficiency of PKD2. Her affected sister also carried the mutation. Family history revealed 6 additional affected family members, but they were not tested for the mutation. In addition to PKD2, the proband had situs inversus totalis, complete inversion of the thoracic large vessels, and a left-sided liver, consistent with a laterality defect. None of her 3 affected sisters had a laterality defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21719175" 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>.0011 POLYCYSTIC KIDNEY DISEASE 2</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> rs398122932 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122932;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/rs398122932?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=rs398122932" 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=rs398122932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033173" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033173" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033173</a>
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<p>In a father and son with polycystic kidney disease-2 (PKD2; <a href="/entry/613095">613095</a>), <a href="#2" class="mim-tip-reference" title="Bataille, S., Demoulin, N., Devuyst, O., Audrezet, M.-P., Dahan, K., Godin, M., Fontes, M., Pirson, Y., Burtey, S. <strong>Association of PKD2 (polycystin 2) mutations with left-right laterality defects.</strong> Am. J. Kidney Dis. 58: 456-460, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719175</a>] [<a href="https://doi.org/10.1053/j.ajkd.2011.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719175">Bataille et al. (2011)</a> identified a heterozygous 3-bp duplication (305_307dupGAG) in exon 1 of the PKD2 gene, resulting in an in-frame insertion of Glu102. The duplication was not reported in 2 large databases. Three sibs of the father were also affected, but mutation analysis was not performed. The duplication was absent in 3 unaffected children of the father. In addition to PKD2, the father had situs inversus and dextrocardia, consistent with a laterality defect. His son and affected sibs did not have laterality defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21719175" 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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Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S., Ehrlich, B. E.
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<strong>Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.</strong>
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Proc. Nat. Acad. Sci. 104: 6454-6459, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17404231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17404231</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17404231[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=17404231" 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.0610324104" target="_blank">Full Text</a>]
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Bataille, S., Demoulin, N., Devuyst, O., Audrezet, M.-P., Dahan, K., Godin, M., Fontes, M., Pirson, Y., Burtey, S.
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<strong>Association of PKD2 (polycystin 2) mutations with left-right laterality defects.</strong>
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Am. J. Kidney Dis. 58: 456-460, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21719175" 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/10.1053/j.ajkd.2011.05.015" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMc0801868" target="_blank">Full Text</a>]
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<strong>PKD1 induces p21-waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2.</strong>
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[<a href="https://doi.org/10.1016/s0092-8674(02)00716-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1078" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.860" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.058149" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.97.8.4017" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp463" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.98.3.1182" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.98.3.790" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1371/journal.pgen.1006070" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M306536200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq355" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.058271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1681/ASN.V9101853" target="_blank">Full Text</a>]
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Viribay, M., Hayashi, T., Telleria, D., Mochizuki, T., Reynolds, D. M., Alonso, R., Lens, X. M., Moreno, F., Harris, P. C., Somlo, S., San Millan, J. L.
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<strong>Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene.</strong>
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Hum. Genet. 101: 229-234, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9402976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9402976</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9402976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050621" target="_blank">Full Text</a>]
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<a id="Watnick2000" class="mim-anchor"></a>
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Watnick, T., He, N., Wang, K., Liang, Y., Parfrey, P., Hefferton, D., St. George-Hyslop, P., Germino, G., Pei, Y.
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<strong>Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations.</strong>
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Nature Genet. 25: 143-144, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835625</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835625" 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/10.1038/75981" target="_blank">Full Text</a>]
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<a id="Wu1998" class="mim-anchor"></a>
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Wu, G., D'Agati, V., Cai, Y., Markowitz, G., Park, J. H., Reynolds, D. M., Maeda, Y., Le, T. C., Hou, H., Jr., Kucherlapati, R., Edelmann, W., Somlo, S.
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<strong>Somatic inactivation of Pkd2 results in polycystic kidney disease.</strong>
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Cell 93: 177-188, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9568711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9568711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9568711" 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/s0092-8674(00)81570-6" target="_blank">Full Text</a>]
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<a id="Wu2000" class="mim-anchor"></a>
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Wu, G., Markowitz, G. S., Li, L., D'Agati, V. D., Factor, S. M., Geng, L., Tibara, S., Tuchman, J., Cai, Y., Park, J. H., van Adelsberg, J., Hou, H., Jr., Kucherlapati, R., Edelmann, W., Somlo, S.
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<strong>Cardiac defects and renal failure in mice with targeted mutations in Pkd2.</strong>
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Nature Genet. 24: 75-78, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615132</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10615132" 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/10.1038/71724" target="_blank">Full Text</a>]
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<a id="Wu1997" class="mim-anchor"></a>
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Wu, G., Mochizuki, T., Le, T. C., Cai, Y., Hayashi, T., Reynolds, D. M., Somlo, S.
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<strong>Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2.</strong>
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Genomics 45: 220-223, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9339380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9339380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9339380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4920" target="_blank">Full Text</a>]
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<a id="Wu2002" class="mim-anchor"></a>
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Wu, G., Tian, X., Nishimura, S., Markowitz, G. S., D'Agati, V., Park, J. H., Yao, L., Li, L., Geng, L., Zhao, H., Edelmann, W., Somlo, S.
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<strong>Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease.</strong>
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Hum. Molec. Genet. 11: 1845-1854, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140187</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140187" 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/11.16.1845" target="_blank">Full Text</a>]
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<a id="Xenophontos1997" class="mim-anchor"></a>
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Xenophontos, S., Constantinides, R., Hayashi, T., Mochizuki, T., Somlo, S., Pierides, A., Constantinou Deltas, C.
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<strong>A transition frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PKD2).</strong>
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Hum. Molec. Genet. 6: 949-952, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9175744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9175744</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9175744" 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/6.6.949" target="_blank">Full Text</a>]
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<a id="Yoshiba2012" class="mim-anchor"></a>
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Yoshiba, S., Shiratori, H., Kuo, I. Y., Kawasumi, A., Shinohara, K., Nonaka, S., Asai, Y., Sasaki, G., Belo, J. A., Sasaki, H., Nakai, J., Dworniczak, B., Ehrlich, B. E., Pennekamp, P., Hamada, H.
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<strong>Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2.</strong>
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Science 338: 226-231, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22983710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22983710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22983710[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=22983710" 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.1222538" target="_blank">Full Text</a>]
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<a id="Zhang2009" class="mim-anchor"></a>
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Zhang, P., Luo, Y., Chasan, B., Gonzalez-Perrett, S., Montalbetti, N., Timpanaro, G. A., del Rocio Cantero, M., Ramos, A. J., Goldmann, W. H., Zhou, J., Cantiello, H. F.
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<strong>The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1.</strong>
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Hum. Molec. Genet. 18: 1238-1251, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19193631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19193631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19193631[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=19193631" 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/ddp024" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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Ada Hamosh - updated : 11/20/2018
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<div class="row collapse" id="mimCollapseContributors">
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George E. Tiller - updated : 09/12/2017<br>Patricia A. Hartz - updated : 11/02/2016<br>Patricia A. Hartz - updated : 1/15/2014<br>Cassandra L. Kniffin - updated : 7/1/2013<br>Cassandra L. Kniffin - updated : 2/21/2013<br>Ada Hamosh - updated : 11/2/2012<br>Patricia A. Hartz - updated : 7/23/2012<br>Patricia A. Hartz - updated : 11/23/2011<br>Patricia A. Hartz - updated : 8/10/2011<br>George E. Tiller - updated : 11/12/2010<br>Patricia A. Hartz - updated : 12/10/2009<br>Patricia A. Hartz - updated : 11/12/2009<br>Matthew B. Gross - updated : 10/16/2009<br>George E. Tiller - updated : 10/14/2009<br>Patricia A. Hartz - updated : 8/15/2008<br>Marla J. F. O'Neill - updated : 7/23/2008<br>George E. Tiller - updated : 6/16/2008<br>Patricia A. Hartz - updated : 7/2/2007<br>Patricia A. Hartz - updated : 4/7/2006<br>Patricia A. Hartz - updated : 6/2/2005<br>George E. Tiller - updated : 5/5/2005<br>Patricia A. Hartz - updated : 1/6/2005<br>George E. Tiller - updated : 7/8/2003<br>Victor A. McKusick - updated : 1/13/2003<br>Victor A. McKusick - updated : 10/11/2002<br>George E. Tiller - updated : 9/6/2002<br>Patricia A. Hartz - updated : 7/1/2002<br>Patricia A. Hartz - updated : 7/1/2002<br>Stylianos E. Antonarakis - updated : 5/1/2002<br>Patricia A. Hartz - updated : 4/30/2002<br>Victor A. McKusick - updated : 7/24/2001<br>Victor A. McKusick - updated : 3/5/2001<br>Victor A. McKusick - updated : 3/1/2001<br>Ada Hamosh - updated : 12/23/2000<br>Victor A. McKusick - updated : 5/26/2000<br>Victor A. McKusick - updated : 3/7/2000<br>Victor A. McKusick - updated : 2/23/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Victor A. McKusick - updated : 12/27/1999<br>Victor A. McKusick - updated : 3/19/1999<br>Victor A. McKusick - updated : 3/11/1999<br>Victor A. McKusick - updated : 2/24/1999<br>Victor A. McKusick - updated : 7/10/1998<br>Stylianos E. Antonarakis - updated : 5/15/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 10/14/1997<br>Victor A. McKusick - updated : 9/23/1997<br>Victor A. McKusick - updated : 7/16/1997<br>Victor A. McKusick - updated : 6/23/1997<br>Victor A. McKusick - updated : 6/2/1997<br>Moyra Smith - updated : 6/6/1996
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<span class="mim-text-font">
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Victor A. McKusick : 9/20/1988
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alopez : 11/20/2018
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carol : 02/08/2018<br>carol : 12/20/2017<br>alopez : 09/12/2017<br>carol : 07/27/2017<br>carol : 04/26/2017<br>carol : 04/25/2017<br>mgross : 11/02/2016<br>carol : 08/27/2016<br>carol : 08/26/2016<br>mgross : 01/17/2014<br>mcolton : 1/15/2014<br>carol : 12/20/2013<br>carol : 7/2/2013<br>ckniffin : 7/1/2013<br>carol : 2/25/2013<br>ckniffin : 2/21/2013<br>terry : 11/13/2012<br>alopez : 11/6/2012<br>alopez : 11/6/2012<br>terry : 11/2/2012<br>mgross : 9/6/2012<br>terry : 7/23/2012<br>mgross : 12/12/2011<br>terry : 11/23/2011<br>mgross : 8/11/2011<br>mgross : 8/11/2011<br>terry : 8/10/2011<br>alopez : 4/21/2011<br>wwang : 11/18/2010<br>terry : 11/12/2010<br>mgross : 12/10/2009<br>terry : 12/10/2009<br>mgross : 12/7/2009<br>terry : 11/12/2009<br>mgross : 10/16/2009<br>terry : 10/14/2009<br>terry : 2/6/2009<br>mgross : 8/19/2008<br>terry : 8/15/2008<br>wwang : 7/23/2008<br>terry : 7/23/2008<br>wwang : 6/19/2008<br>terry : 6/16/2008<br>wwang : 7/6/2007<br>terry : 7/2/2007<br>carol : 6/9/2006<br>mgross : 4/14/2006<br>terry : 4/7/2006<br>wwang : 6/6/2005<br>terry : 6/2/2005<br>wwang : 5/27/2005<br>tkritzer : 5/5/2005<br>mgross : 1/14/2005<br>terry : 1/6/2005<br>mgross : 3/17/2004<br>tkritzer : 2/5/2004<br>cwells : 7/8/2003<br>alopez : 2/25/2003<br>alopez : 1/13/2003<br>alopez : 1/13/2003<br>tkritzer : 10/28/2002<br>tkritzer : 10/17/2002<br>terry : 10/11/2002<br>cwells : 9/6/2002<br>carol : 7/1/2002<br>carol : 7/1/2002<br>mgross : 5/1/2002<br>carol : 4/30/2002<br>carol : 4/30/2002<br>mcapotos : 8/8/2001<br>mcapotos : 7/31/2001<br>terry : 7/24/2001<br>mcapotos : 3/9/2001<br>mcapotos : 3/7/2001<br>terry : 3/5/2001<br>terry : 3/1/2001<br>carol : 12/23/2000<br>mcapotos : 8/3/2000<br>mcapotos : 8/3/2000<br>alopez : 5/30/2000<br>joanna : 5/26/2000<br>mcapotos : 4/3/2000<br>mcapotos : 3/21/2000<br>terry : 3/7/2000<br>terry : 2/28/2000<br>carol : 2/23/2000<br>mgross : 2/3/2000<br>terry : 1/11/2000<br>alopez : 12/29/1999<br>terry : 12/27/1999<br>mgross : 3/29/1999<br>mgross : 3/26/1999<br>terry : 3/19/1999<br>carol : 3/16/1999<br>terry : 3/11/1999<br>terry : 3/9/1999<br>terry : 2/24/1999<br>carol : 7/15/1998<br>terry : 7/10/1998<br>carol : 5/19/1998<br>dholmes : 5/15/1998<br>dholmes : 5/15/1998<br>mark : 12/9/1997<br>terry : 12/2/1997<br>jenny : 10/17/1997<br>terry : 10/14/1997<br>terry : 9/23/1997<br>mark : 7/16/1997<br>terry : 7/10/1997<br>terry : 7/10/1997<br>jenny : 6/27/1997<br>jenny : 6/23/1997<br>terry : 6/19/1997<br>mark : 6/2/1997<br>mark : 2/23/1997<br>terry : 12/10/1996<br>mark : 10/17/1996<br>terry : 10/10/1996<br>mark : 7/20/1996<br>mark : 6/17/1996<br>terry : 6/13/1996<br>carol : 6/6/1996<br>mark : 8/9/1995<br>mimadm : 2/25/1995<br>carol : 2/1/1995<br>carol : 12/17/1993<br>carol : 12/2/1993<br>carol : 11/29/1993
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<span class="mim-font">
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<strong>*</strong> 173910
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POLYCYSTIN 2; PKD2
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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PKD2 GENE<br />
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PC2<br />
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TRPP2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PKD2</em></strong>
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<strong>SNOMEDCT:</strong> 253879006;
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Cytogenetic location: 4q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:88,007,635-88,077,777 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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4q22.1
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Polycystic kidney disease 2
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613095
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The PKD2 gene encodes polycystin-2, which belongs to the superfamily of transient receptor potential (TRP) channels. Polycystin-2 is a large-conductance, Ca(2+)-permeable nonselective cation channel involved in Ca(2+) transport and Ca(2+) signaling in renal epithelial cells (Zhang et al., 2009). PKD2 localizes to cilia and functions as a mechanotransducer that stimulates an increase in intracellular calcium in response to fluid flow (Nauli et al., 2003). Like other prototypical TRP channels, polycystin-2 has 6 transmembrane domains and cytoplasmic N and C termini. TRP channels, including polycystin-2, assemble as homo- and heteromultimers, particularly tetramers, and this heteromerization is thought to provide functional and regulatory diversity among channel complexes (Zhang et al., 2009). </p>
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<strong>Cloning and Expression</strong>
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<p>Mochizuki et al. (1996) reported the isolation and characterization of a candidate gene for polycystic kidney disease-2 (PKD2; 613095) on chromosome 4. They initially refined the mapping of the PKD2 gene within an interval of 680 kb. They then used genomic clones from this interval to isolate cDNA clones. One of these clones revealed homology at the amino acid level with polycystin, the PKD1 gene product (601313). This clone was used to isolate a series of overlapping cDNA clones that encompassed the candidate gene. The gene contains a 2,904-bp open reading frame and a 2,086-bp untranslated region. It is strongly expressed in ovary, fetal and adult kidney, testis, and small intestine. Mochizuki et al. (1996) detected no expression of the gene in peripheral leukocytes. The predicted translation product is a 968-amino acid polypeptide which appears to be an integral membrane protein with 6 membrane-spanning domains and intracellular N and C termini. There is 25% identity and 50% similarity between the putative translation product of PKD2 and the 450-amino acid product of PKD1. There is a similar degree of homology between the putative PKD2 locus product and that of the voltage-activated calcium channel-alpha-1E gene (see 601012). </p><p>Schneider et al. (1996) likewise cloned the PKD2 gene. </p>
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<strong>Gene Structure</strong>
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<p>Mochizuki et al. (1996) determined that the PKD2 gene extends over 68 kb. </p><p>Hayashi et al. (1997) found that the PKD2 gene has at least 15 exons with the translation start site in exon 1. All the splice acceptor and donor sites conform to the AG/GT rule. </p><p>Lantinga-van Leeuwen et al. (2005) determined that the promoter region of both the PKD1 and PKD2 genes are TATA-less, but they have binding sites for E2F (see 189971), EGRF (see EGR1; 128990), ETS (see 600541), MZF1 (194550), SP1 (189906), and ZBP89 (601867). </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Cryoelectron Microscopy Structure</em></strong></p><p>
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Su et al. (2018) reported the 3.6-angstrom cryoelectron microscopy structure of truncated human PKD1 (601313)-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical transient receptor potential channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the voltage-gated ion channel, a 5-transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Using a YAC contig and STS map of the PKD2 region on chromosome 4, Mochizuki et al. (1996) mapped the PKD2 gene to chromosome 4q21-q23. </p>
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<strong>Gene Function</strong>
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<p>It was suggested that the different forms of autosomal dominant polycystic kidney disease, PKD1 and PKD2, and perhaps a third form result from defects in interactive factors involved in a common pathway. The discovery of the genes for the 2 most common forms of ADPKD provided an opportunity to test this hypothesis. Qian et al. (1997) described a previously unrecognized coiled-coil domain within the C terminus of the PKD1 gene product, polycystin-1, and demonstrated that it binds specifically to the C terminus of PKD2. Homotypic interactions involving the C terminus of each were also demonstrated. They showed that naturally occurring pathogenic mutations of PKD1 and PKD2 disrupt their associations. Qian et al. (1997) suggested that PKD1 and PKD2 associate physically in vivo and may be partners of a common signaling cascade involved in tubular morphogenesis. </p><p>Tsiokas et al. (1997) showed that PKD1 and PKD2 interact through their C-terminal cytoplasmic tails. This interaction results in upregulation of PKD1 but not PKD2. Furthermore, the cytoplasmic tail of PKD2 but not PKD1 forms homodimers through a coiled-coil domain distinct from the region required for interaction with PKD1. These interactions suggested that PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis and that PKD1 requires the presence of PKD2 for stable expression. </p><p>PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell-to-cell or cell-matrix interactions, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein. Hanaoka et al. (2000) demonstrated that polycystin-1 and -2 interact to produce new calcium-permeable nonselective cation currents. Neither polycystin-1 nor polycystin-2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization through the coiled-coil domain do not result in new channel activity. Hanaoka et al. (2000) also showed that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 coassemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function. </p><p>Koulen et al. (2002) investigated subcellular localization and calcium channel activity of PKD2 by overexpressing the full-length gene, a C-terminal truncated polycystin-2 mutant, and the asp511-to-val mutation (D522V; 173910.0008) in porcine kidney cells. They found that polycystin-2 localizes to the endoplasmic reticulum (ER) and behaves as a calcium-activated, high conductance channel that is permeable to divalent cations. The C-terminal truncated mutant had no significant channel activity and showed altered subcellular localization caused by loss of the essential ER retention signal. The D511V variant retained ER subcellular localization, normal protein interaction, and the regulatory domains of the wildtype protein, but had loss of channel activity. </p><p>Gonzalez-Perrett et al. (2001) demonstrated that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states and a high perm-selectivity to calcium ions. This channel was inhibited by antipolycystin-2 antibody and the diuretic amiloride. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD. Grantham and Calvet (2001) reviewed observations suggesting that the polycystins regulate cell proliferation. They stated that 'it seems more likely that the polycystins will be found to be involved in the abnormal regulation of tubular epithelial cell proliferation rather than the transepithelial transport of electrolytes and water.' </p><p>Using polyclonal antisera raised against polycystin-2, Scheffers et al. (2002) demonstrated distinct expression of the endogenous polycystin-2 in the Golgi apparatus and the plasma membrane of MDCK cells. In contrast, most of the heterologously expressed polycystin-2-EGFP fusion protein remained in the ER, substantially overlapping with the staining pattern of protein-disulfide isomerase (PDI; 176790), a marker for the ER. In a small subset of cells, weak plasma membrane signals were observed by immunoelectron microscopy and Western blotting of subcellular fractions. The plasma membrane staining disappeared following extraction with a mild detergent, suggesting that polycystin-2 is not tightly bound to the insoluble cytoskeleton, nor to polycystin-1. The authors concluded that endogenous polycystin-2 is transported via the Golgi apparatus to the plasma membrane and has a broader membrane localization than polycystin-1. </p><p>Bhunia et al. (2002) showed that expression of polycystin-1 activates the JAK (see 147795)-STAT (see STAT1; 600555) pathway, thereby upregulating WAF1 (CDKN1A; 116899) and inducing cell cycle arrest in G0/G1. They found that this process requires polycystin-2 as an essential cofactor. Mutations that disrupted binding of polycystin-1 and -2 prevented activation of the pathway. Mouse embryos lacking Pkd1 had defective STAT1 phosphorylation and Waf1 induction. These results suggested that 1 function of the complex of polycystin-1 and -2 is to regulate the JAK-STAT pathway and explained how mutations of either gene can result in dysregulated growth. </p><p>Using coimmunoprecipitation and cosedimentation techniques, Newby et al. (2002) found that 7 to 8% of polycystin-2 colocalizes with polycystin-1 in plasma membrane fractions of both normal human kidney and mouse kidney cells transgenic for human PKD1. Polycystin-2 is a glycoprotein with 5 putative N-glycosylation sites; it is endoglycosidase H (Endo H)-sensitive, indicating that the mature protein contains high mannose-type oligosaccharides. Polycystin-1 is heavily N-glycosylated and contains both Endo-H sensitive and mature Endo-H-resistant forms, both of which are able to interact with polycystin-2. Newby et al. (2002) interpreted these results to suggest early association of the 2 proteins in the ER/cis-Golgi prior to insertion into the plasma membrane. </p><p>Grimm et al. (2003) found that mammalian polycystin-1 localized to the cell surface and ER in cells that did not express polycystin-2. However, when the 2 proteins were coexpressed in the same cell line, polycystin-1 colocalized exclusively with polycystin-2 in the ER. Further work indicated that the subcellular localization of polycystin-1 depended on the ratio of polycystin-2 to polycystin-1 expression and that the localization of polycystin-1 could be regulated via the relative expression level of polycystin-2. </p><p>Luo et al. (2003) found endogenous polycystin-2 expressed in the plasma membrane and the primary cilium of mouse inner medullar collecting duct cells and in canine kidney cells, whereas heterologously expressed polycystin-2 showed a predominant ER localization. Patch-clamping of inner medullar collecting duct cells expressing endogenous or heterologous polycystin-2 confirmed the presence of the channel on the plasma membrane. Treatment with chaperone-like factors facilitated the translocation of the polycystin-2 channel to the plasma membrane from intracellular pools. Luo et al. (2003) concluded that polycystin-2 functions as a plasma membrane channel in renal epithelia and that it contributes to Ca(2+) entry and transport of other cations in defined nephron segments in vivo. </p><p>The PKD1 and PKD2 proteins' interaction with each other through their C termini suggests that the 2 proteins are part of the same protein complex or signal transduction pathway. Using a yeast 2-hybrid screen with the PKD2 protein, Gallagher et al. (2000) isolated the PKD2-interacting protein HAX1 (605998). Specificity of the interaction was demonstrated by the failure of PKD2L (604532), a protein closely related to PKD2, to interact with HAX1. Immunofluorescence experiments showed that in most cells PKD2 and HAX1 colocalized in the cell body, but in some cells they also were sorted into cellular processes and lamellipodia. Gallagher et al. (2000) demonstrated an association between HAX1 and the F-actin-binding protein cortactin (164765), which suggested a link between PKD2 and the actin cytoskeleton. Gallagher et al. (2000) speculated that PKD2 is involved in the formation of cell-matrix contacts, which are dysfunctional without a wildtype PKD2 protein, thus leading to cystic enlargement of tubular structures in the kidney, liver, and pancreas. </p><p>Nauli et al. (2003) showed that polycystin-1 and polycystin-2 in mice codistribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lacked functional polycystin-1 formed cilia but did not increase Ca(2+) influx in response to physiologic fluid flow. Blocking antibodies directed against polycystin-2 similarly abolished the flow response in wildtype cells as did inhibitors of the ryanodine receptor (RYR1; 180901), whereas inhibitors of G proteins, phospholipase C (see 600220), and inositol 1,4,5-trisphosphate receptors had no effect. These data suggested that polycystin-1 and polycystin-2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of polycystin-1 or polycystin-2 may therefore lead to polycystic kidney disease owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis. Calvet (2003) reproduced a scanning electron micrograph of the inside of a collecting-duct cyst from a human autosomal dominant polycystic kidney, showing a single intercalated cell surrounded by principal cells, each with 1 or several primary cilia. Although the cilia on these cells appeared normal, they were presumably functionally defective because of the mutation in the PKD1 or PKD2 gene. </p><p>By yeast 2-hybrid analysis, Li et al. (2005) showed that both intracellular N and C termini of polycystin-2 associated with alpha-actinins (see 102575), actin-binding, and actin-bundling proteins. In vivo interaction between endogenous polycystin-2 and alpha-actinins was demonstrated by coimmunoprecipitation in human, canine, and rodent cell lines. Immunofluorescence experiments showed that polycystin-2 and alpha-actinin were partially colocalized in canine epithelial kidney, murine inner medullary collecting duct cells and fibroblasts, and human syncytiotrophoblast vesicles. Alpha-actinin substantially stimulated the channel activity of reconstituted polycystin-2 in a lipid bilayer system. Li et al. (2005) hypothesized that physical and functional interactions between polycystin-2 and alpha-actinin may play an important role in abnormal cell adhesion, proliferation, and migration observed in ADPKD. </p><p>Li et al. (2005) found that polycystin-2 overexpression in human embryonic kidney cells led to reduced cell proliferation. They showed that polycystin-2 interacted directly with ID2 (600386) and modulated the cell cycle via the ID2-CDKN1A-CDK2 (116953) pathway. The ID2-polycystin-2 interaction caused sequestration of ID2 in the cytoplasm and required polycystin-1-dependent serine phosphorylation of polycystin-2. Kidney epithelial cells from a mouse model of PKD1 showed abnormalities in the cell cycle that could be reversed by RNA interference-mediated inhibition of Id2 mRNA expression. </p><p>Anyatonwu et al. (2007) stated that polycystin-2 interacts with several integral membrane proteins, including TRPC1 (602343) and InsP3R (ITPR1; 147265). They found that mouse Pkd2 coimmunoprecipitated with the cardiac ryanodine receptor Ryr2 (180902) from mouse heart. Biochemical assays showed that the N terminus of Pkd2 bound Ryr2, whereas the C terminus only bound to Ryr2 in its open state. Lipid bilayer electrophysiologic experiments indicated that the C terminus of Pkd2 functionally inhibited Ryr2 channel activity in the presence of Ca(2+). </p><p>Li et al. (2008) showed that TNF-alpha (191160), which is found in cystic fluid of humans with ADPKD, disrupted the localization of polycystin-2 to the plasma membrane and primary cilia through the TNF-alpha-induced scaffold protein FIP2 (OPTN; 602432). Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in cyst formation, and this effect was exacerbated in Pkd2 +/- kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2 +/- mice, and treatment of Pkd2 +/- mice with a TNF-alpha inhibitor prevented cyst formation. </p><p>In a kinetic analysis of spontaneous channel currents of PC2, Zhang et al. (2009) showed that 4 intrinsic, non-stochastic subconductance states, which followed a staircase behavior, were both pH and voltage dependent. Low pH inhibited PC2 currents in PC2 homomeric complexes, but failed to affect PC2 currents in PC2/TRPC1 heteromeric complexes. In contrast, amiloride abolished PC2 currents in both homomeric PC2 complexes and heteromeric PC2/TRPC1 complexes, indicating that PC2/TRPC1 complexes have distinct functional properties from the homomeric complexes. The topologic features of the homomeric PC2 and TRPC1 complexes and the heteromeric PC2/TRPC1 complex were consistent with structural tetramers. Zhang et al. (2009) proposed tetrameric models for both the PC2 and TRPC1 channels, where the overall conductance of a particular channel depends on the contributions of the various functional monomers in the complex. </p><p>Liang et al. (2008) showed that wildtype and C-terminally truncated mutants of PC2 that cause PKD2 were eliminated by ER-associated degradation (ERAD) via the ubiquitin-proteasome system. Both N- and C-terminal regions of PC2 interacted with HERP (HERPUD1; 608070), and this interaction was required for PC2 degradation. PC2 lacking both N and C termini did not interact with HERP and was not degraded. </p><p>ER stress increases the kinase activity of PERK (EIF2AK3; 604032) to promote EIF2-alpha (EIF2S1; 603907) phosphorylation, which results in translational repression and reduced cell growth. Using several mammalian cell lines, including human cell lines, in overexpression and knockdown studies, Liang et al. (2008) showed that PC2 downregulated cell proliferation through the PERK-EIF2-alpha signaling pathway. Coimmunoprecipitation experiments revealed that PC2 interacted in a complex with PERK and EIF2-alpha. </p><p>Sharif-Naeini et al. (2009) showed that mouse Pkd1 and Pkd2, which they called Trpp1 and Trpp2, could regulate stretch-activated ion channels and were involved in pressure sensing. </p><p>Tran et al. (2010) found that embryonic Bicc1 (614295) -/- mice developed severely polycystic kidneys on both sides, as well as liver and pancreatic cysts and defects in left-right patterning. Quantitative PCR showed progressive downregulated expression of Pkd2, but not Pkd1 or Pkhd1 (606702), between embryonic days 15.5 and 18.5 in Bicc1 -/- kidneys compared with wildtype kidneys. Pkd2 expression was also lower than normal in Bicc1 +/- mouse kidneys and following morpholino-mediated Bicc1 knockdown in Xenopus larvae. Examination of the 3-prime UTR of Pkd2 transcripts revealed a target site for the Mir17 (see 609416) family of microRNAs. Mutation within the Mir17-binding site reversed Pkd2 downregulation following Bicc1 knockdown in Xenopus larvae. Furthermore, expression of Mir17 duplexes reduced expression of Pkd2 3-prime UTR reporter genes, whereas expression of Bicc1 increased Pkd2 expression. Tran et al. (2010) concluded that BICC1 regulates PKD2 expression by countering the inhibitory effect of MIR17. </p><p>Yoshiba et al. (2012) reported that the calcium ion channel polycystin-2 is required specifically in the perinodal crown cells for the sensing of nodal flow. Examination of mutant forms of Pkd2 showed that the ciliary localization of Pkd2 is essential for correct left-right patterning. Whereas Kif3a (604683) mutant embryos, which lack all cilia, failed to respond to an artificial flow, restoration of primary cilia in crown cells rescued the response to the flow. Yoshiba et al. (2012) concluded that their results suggested that nodal flow is sensed in a manner dependent on Pkd2 by the cilia of crown cells located at the edge of the node. </p><p>Using mutant mouse cells and embryos, Grimes et al. (2016) found that Pkd1l1 (609721) and Pkd2 required the ciliary structure to function and that Pkd1l1 was at least partially involved in Pkd2 localization to cilia. Pkd2 elicited bilateral Nodal gene expression in the absence of Pkd1l1. Grimes et al. (2016) hypothesized that PKD1L1 represses PKD2 in the node and that nodal flow relieves this repression on the left side only, activating PKD2 and initiating a signaling cascade that results in left-sided NODAL activity. </p><p>Hurd et al. (2010) observed that RP2 (300757) formed a calcium-sensitive complex with PKD2 in renal epithelia. Ablation of RP2 by short hairpin RNA (shRNA) promoted swelling of the cilia tip that could represent aberrant trafficking of PKD2 and other ciliary proteins. In addition to the observed physical interaction between RP2 and PKD2, dual morpholino-mediated knockdown of PKD2 and RP2 resulted in enhanced situs inversus, indicating that these 2 genes may regulate a common developmental process. The authors suggested that RP2 may be an important regulator of ciliary function through its association with PKD2, and provided evidence of a further link between retinal and renal cilia function. </p>
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<strong>Molecular Genetics</strong>
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<p>Mochizuki et al. (1996) analyzed the PKD2 gene in affected individuals in 3 families with type-2 polycystic kidney disease (PKD2; 613095). They used reverse-transcribed RNA and genomic DNA templates to generate PCR products for SSCP analysis and sequencing. Three nonsense mutations in the PKD2 gene were identified in affected individuals; see 173910.0001, 173910.0002, and 173910.0003. These mutations were not present in controls. </p><p>Viribay et al. (1997) used heteroduplex and SSCP analyses in a systematic mutation screening of all 15 exons of the PKD2 gene in chromosome 4-linked ADPKD families, They identified and characterized 7 novel mutations, with a detection rate of approximately 90% in the populations studied. All of the mutations resulted in the premature stop of translation: 4 nonsense changes (e.g., 173910.0005) and 3 deletions. The deletions were all frameshifting, of 4 T nucleotides in 1 case and 1 G nucleotide in the other 2. All the mutations were unique and were distributed throughout the gene without evidence of clustering. Comparison of specific mutations with a clinical profile in these families showed no clear correlation. </p><p>Veldhuisen et al. (1997) systematically screened the PKD2 gene for mutations by SSCP analysis in 35 families with ADPKD and identified 20 mutations. </p><p>Pei et al. (1998) screened for PKD2 mutations in 11 Canadian families with ADPKD. In 4 families, linkage to PKD2 had been documented; in the remaining 7 smaller families, one or more affected members had late-onset end-stage renal disease at age 70 or older, a feature suggesting PKD2. Parfrey et al. (1990) and Ravine et al. (1992) had found a mean age of onset of ESRD among affected members in PKD1-linked families to be 56 years; in contrast, the mean age of onset of ESRD among affected members in PKD2-linked families was 70 years. Pei et al. (1998) found mutations in 8 of the 11 families, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In 3 unrelated families, insertion or deletion of an adenosine in a polyadenosine tract, (A)8 at nucleotides 2152-2159, was found in exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from 'slipped strand mispairing.' All the mutations, scattered between exons 1 and 11, were predicted to result in a truncated polycystin-2 that lacks both the calcium-binding EF-hand domain and the 2 cytoplasmic domains required for the interaction of polycystin-2 with polycystin-1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. </p><p>In both kidneys of a patient with PKD2, Koptides et al. (1999) identified, for the first time, multiple novel somatic mutations within the PKD2 gene of epithelial cells. The family involved in this case had previously been shown to possess a 1-bp insertion (173910.0004) as the germline mutation. In 7 (33%) of 21 cysts examined, the authors identified a different 1-bp insertion (173910.0007) within the inherited wildtype allele. In 2 other cysts, a nonsense mutation and a splice site deletion had occurred in a PKD2 allele that could not be identified as the inherited wildtype or mutant. Koptides et al. (1999) suggested that the autosomal dominant form of PKD2 occurs by a cellular recessive mechanism, supporting a 2-hit model for cyst formation. </p><p>Koptides et al. (2000) provided the first direct genetic evidence that polycystins 1 and 2 interact, perhaps as part of a larger complex. In cystic DNA from a kidney of a patient with autosomal dominant PKD1, the authors showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a transheterozygous state with mutations in both genes. The mutation in PKD1 was of germinal nature and the mutation in PKD2 was of somatic nature. The authors stated that to their knowledge there was no precedent to the transheterozygous model as a mechanism for human disease development. </p><p>Watnick et al. (2000) found somatic mutations of PKD2 in 71% of ADPKD2 cysts analyzed. They found clonal somatic mutations of PKD1 in a subset of cysts that lacked PKD2 mutations. In 10 cysts, they demonstrated that the wildtype PKD2 allele had acquired the mutation. They found 3 PKD2 cysts with somatic PKD1 mutations in each cyst; comprehensive screening of the entire PKD2 coding sequence was negative. They referred to this as a pathogenic effect of transheterozygous mutations. </p><p>Torra et al. (1999) sought to demonstrate that somatic mutations are present in renal cysts from a PKD2 kidney. They studied 30 renal cysts from a patient with PKD2 in whom the germline mutation was shown to be a deletion that encompassed most of the gene. Loss of heterozygosity (LOH) studies showed loss of a wildtype allele in 10% of cysts. Screening of 6 exons of the gene by SSCP detected 8 different somatic mutations, all of which were expected to produce truncated proteins. Overall, more than 37% of the cysts studied represented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 on chromosome 3 was observed in those cysts, which demonstrated that somatic alterations were specific. </p><p>Pei et al. (2001) reported studies of an extensively affected Newfoundland family in which it appeared that there was bilineal disease from independently segregating PKD1 and PKD2 mutations. A PKD2 mutation (2152delA; L736X) was found in 12 affected pedigree members. In addition, when the disease status of these individuals was coded as unknown in linkage analysis, they found, with markers at the PKD1 locus, significant lod scores, i.e., greater than 3.0. The findings strongly supported the presence of a PKD1 mutation in 15 other affected pedigree members, who lacked the PKD2 mutation. Two additional affected individuals had transheterozygous mutations involving both genes, and they had renal disease that was more severe than that in affected individuals who had either mutation alone. This was said to be the first demonstration of bilineal disease in ADPKD. In humans, transheterozygous mutations involving both PKD1 and PKD2 are not necessarily embryonically lethal. The authors concluded that the presence of bilineal disease as a confounder needs to be considered in the search for the PKD3 locus. </p><p>In affected members of 2 unrelated families with polycystic kidney disease, Bataille et al. (2011) identified 2 different heterozygous mutations in the PKD2 gene (173910.0010 and 173910.0011). In addition to kidney disease, the proband from each of the families also showed laterality defects, including situs inversus and dextrocardia, that were not seen in other affected family members. A third proband with PKD2 and a large 80-kb deletion involving PKD2 and ABCG2 (603756) also had laterality defects. The findings suggested that laterality defects may occur in some patients with PKD2 mutations, as has been demonstrated in animal models (see, e.g., Pennekamp et al., 2002). </p>
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<h4>
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<strong>Animal Model</strong>
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<p>Wu et al. (1997) cloned the murine homolog, Pkd2, and mapped it to mouse chromosome 5. The map location excluded it as a candidate gene for previously mapped mouse mutations resulting in a polycystic kidney phenotype. </p><p>Wu et al. (1998) introduced a mutant exon 1 in tandem with the wildtype exon 1 at the mouse Pkd2 locus. This was an unstable allele that underwent somatic inactivation by intragenic homologous recombination to produce a true null Pkd2 allele. Mice heterozygous and homozygous for this mutation develop polycystic kidney and liver lesions that are indistinguishable from the human phenotype. In all cases, renal cysts arise from renal tubular cells that lose the capacity to produce Pkd2 protein. Wu et al. (1998) concluded that somatic loss of Pkd2 expression is both necessary and sufficient for renal cyst formation in ADPKD, suggesting that PKD2 occurs by a cellular recessive mechanism. </p><p>Wu et al. (2000) induced 2 mutations in the mouse homolog Pkd2: an unstable allele that can undergo homologous recombination-based somatic rearrangement to form a null allele; and a true null allele. They examined these mutations to understand the function of polycystin-2 and to provide evidence that kidney and liver cyst formation associated with Pkd2 deficiency occurs by a 2-hit mechanism. They found that Pkd2 -/- mice die in utero between embryonic day (E) 13.5 and parturition. They have structural defects in cardiac septation and cyst formation in maturing nephrons and pancreatic ducts. Pancreatic ductal cysts also occur in adult Pkd2 mice heterozygous for the unstable allele, suggesting that this clinical manifestation of ADPKD also occurs by a 2-hit mechanism. As in human ADPKD, formation of kidney cysts in adult mice heterozygous for the unstable allele is associated with renal failure and early death (median survival, 65 weeks vs 94 weeks for controls). Adult mice heterozygous for the null mutation have intermediate survival despite absence of cystic disease or renal failure, providing the first indication of a deleterious effect of haploinsufficiency at Pkd2 on long-term survival. </p><p>Wu et al. (2002) investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1 +/-, Pkd2 +/-, and Pkd1 +/- : Pkd2 +/- mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the 2-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 +/- mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1 +/- : Pkd2 +/- mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. These data suggested a modifier role for the 'trans' polycystin gene in cystic kidney disease, and supported a contribution from threshold effects to cyst formation and growth. </p><p>In mouse embryos, Pennekamp et al. (2002) found ubiquitous expression of the Pkd2 gene from the 2-cell to the compact blastocyst stage. It was also expressed at the headfold and early somite stages, with higher levels in the floorplate and notocord. Knockout of Pkd2 was embryonic lethal between days E12.5 and birth, and the mutant embryos showed multiple laterality defects. Heterozygous Pkd2 +/- mice also showed laterality defects, including right pulmonary isomerism, randomization of embryonic turning, heart looping, and abdominal situs. There was also lack of expression of Leftb (603037) and Nodal (601265) in the left lateral mesoderm plate, absence of Ebaf (601877) at the floorplate, and lack of Pitx2 (601542) in the left lateral mesoderm anteriorly; all of these genes are involved in the left-right signaling pathway. However, the embryonic midline was present and there were normal levels of Shh (600725). The findings suggested that Pkd2 acts in parallel with or downstream of Shh and upstream of the Nodal cascade. </p><p>Qian et al. (2003) found that the level of polycystin-2 expression in mouse Pkd2 +/- vessels was roughly half that of wildtype and that the level of intracranial vascular abnormalities in Pkd2 +/- mice was enhanced when induced to develop hypertension by unilateral carotid ligation. In addition, Pkd2 +/- vascular smooth muscle cells had significantly altered intracellular calcium homeostasis. The resting intracellular calcium concentration was lower in Pkd2 +/- compared with wildtype cells (p = 0.0003) and the total sarcoplasmic reticulum calcium store was decreased (p less than 0.0001). The store-operated calcium (SOC) channel activity was also decreased in Pkd2 +/- cells (p = 0.008). These results indicated that inactivation of just 1 Pkd2 allele is sufficient to alter significantly intracellular calcium homeostasis and that polycystin-2 may be necessary to maintain normal SOC activity and the sarcoplasmic reticulum calcium store in vascular smooth muscle cells. Qian et al. (2003) concluded that the abnormal intracellular calcium regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype. </p><p>In embryonic mice, McGrath et al. (2003) found expression of the Pkd2 gene in 2 types of cilia at the embryonic node around days E7.0-E8.0 during the period of leftward, ciliary-driven nodal flow that is important in left-right patterning. There appeared to be 2 sets of monocilia at the node: centrally located, motile monocilia containing Pkd2 and the axonemal dynein Dnahc11 (603339), and peripherally located, immotile monocilia containing only Pkd2. Around the time of embryonic nodal flow, there was an asymmetric distribution of intracellular calcium prominent in cells at the left margin of the node, but not at the right margin. Dnahc11-null embryos showed abnormalities in this asymmetric calcium signaling at the node, either left, bilateral, or absent, suggesting randomization. Pkd2-null embryos showed a complete lack of calcium signaling, suggesting that Pkd2 functions as a mechanotransducer of leftward flow into increased calcium signaling. The findings indicated that the 2 types of ciliary proteins coordinate to determine proper left-right signaling in the mouse embryo. </p><p>Anyatonwu et al. (2007) stated that Pkd2-null mice develop cardiovascular abnormalities. They found that cardiomyocytes cultured from mouse embryos lacking Pkd2 exhibited a significantly higher frequency of spontaneous oscillations compared with cells from wildtype embryos, presumably due to relief of Ryr2 (180902) inhibition. In addition, Pkd2-null cardiomyocytes had reduced levels of Ca(2+) in the sarcoplasmic reticulum and subsequently showed reduced amplitude for the Ca(2+) transients compared with wildtype cardiomyocytes. </p><p>Gao et al. (2010) showed that overexpression or depletion of Prkcsh in zebrafish embryos led to pronephric cysts, abnormal body curvature, and situs inversus. Identical phenotypic changes were induced by depletion or overexpression of Pkd2. Increased Prkcsh levels ameliorated developmental abnormalities caused by overexpressed Pk2, whereas excess Pkd2 could compensate the loss of Prkcsh, indicating that the proteins may share a common signaling pathway. Prkcsh bound the C-terminal domain of Pkd2, and both proteins colocalized within the ER. Furthermore, Prkcsh interacted with Herp (HERPUD1; 608070), and inhibited Herp-mediated ubiquitination of Pkd2. Gao et al. (2010) suggested that PRKCSH may function as a chaperone-like molecule, which may prevent ERAD of PKD2. </p><p>Using a combination of targeted knockout and overexpression with 2 genes mutated in polycystic liver disease (PCLD; 174050), Prkcsh (177060) and Sec63 (608648), and 3 genes mutated in polycystic kidney disease, Pkd1, Pkd2, and Pkhd1, Fedeles et al. (2011) produced a spectrum of cystic disease severity in mice. Cyst formation in all combinations of these genes, except complete loss of Pkd2, was significantly modulated by altering expression of Pkd1. Proteasome inhibition increased the steady-state levels of Pkd1 in cells lacking Prkcsh and reduced cystic disease in mouse models of autosomal dominant polycystic liver disease. Fedeles et al. (2011) concluded that PRKCSH, SEC63, PKD1, PKD2, and PKHD1 form an interaction network with PKD1 as the rate-limiting component. </p><p>Kamura et al. (2011) and Field et al. (2011) independently studied mutant medaka fish and mouse embryos, respectively, and found that Pkd2 functionally interacted with Pkd1l1 at nodal cilia. Both proteins were required for normal left-right patterning and gene expression during embryonic development. </p><p>Khonsari et al. (2013) found that mice with conditional deletion of the Pkd2 gene in neural crest-derived cells showed signs of mechanical trauma to craniofacial structures, such as fractured molar roots, distorted incisors, alveolar bone loss, and compressed temporomandibular joints, as well as abnormal skull shapes. The phenotype was not apparent during embryonic stages, suggesting that postnatal mechanical stress is important for the development of these structures. Pkd2 was expressed ubiquitously in craniofacial structures during embryonic stages, but showed more restricted tissue expression after birth. In addition, several aneurysms and enlarged ventricles were found in mutant mouse brains. Three-dimensional photographic analysis of the craniofacial features of 19 human PKD2 patients showed some specific characteristics, including increased facial asymmetry, vertical lengthening of the face and nose, and mild mid-facial hypoplasia. The results suggested that the PKD2 gene plays a role in craniofacial growth as a mechanoreceptor. </p><p>Ma et al. (2013) noted that, like loss of either Pkd1 or Pkd2, loss of cilia following ablation of intraflagellar transport results in cyst formation in animal models. Ma et al. (2013) combined conditional inactivation of Pkd1 or Pkd2 in mice with conditional inactivation of the intraflagellar transport genes Kif3a and Ift20 (614394). They found that structurally intact cilia were required to promote cyst growth following loss of Pkd1 or Pkd2. In contrast, Pkd1 or Pkd2 were not required for cyst development following loss of intraflagellar transport. Furthermore, combined loss of cilia and Pkd1 or Pkd2 significantly slowed cell growth and cyst formation in all mouse nephron segments and in liver. Ma et al. (2013) concluded that PKD1 and PKD2 inhibit a cilia-dependent proliferative pathway that results in cyst formation. This signaling pathway appeared to be independent of signaling through MAPK/ERK, MTOR (601231), or cAMP. </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>11 Selected Examples):</strong>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>.0001 POLYCYSTIC KIDNEY DISEASE 2</strong>
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</span>
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</h4>
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PKD2, TRP380TER
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<br />
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SNP: rs121918039,
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ClinVar: RCV000014472
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<p>In affected members of a family (family 97) with chromosome 4-linked polycystic kidney disease-2 (PKD2; 613095), Mochizuki et al. (1996) identified a G-to-A transition in the PKD2 gene that resulted in a change at codon 380 from trp to stop. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 POLYCYSTIC KIDNEY DISEASE 2</strong>
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</span>
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PKD2, ARG742TER
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SNP: rs121918040,
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gnomAD: rs121918040,
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ClinVar: RCV000014473, RCV000518276, RCV000654888
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<p>In affected members of a Cypriot family (family 1605) with chromosome 4-linked polycystic kidney disease-2 (PKD2; 613095), Mochizuki et al. (1996) identified a C-to-T transition in the PKD2 gene that resulted in a change at codon 740 from arg to stop. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 POLYCYSTIC KIDNEY DISEASE 2</strong>
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PKD2, GLN405TER
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SNP: rs121918041,
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ClinVar: RCV000014474
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<p>In a second unrelated Cypriot family (family 1601) with chromosome 4-linked polycystic kidney disease-2 (PKD2; 613095), Mochizuki et al. (1996) identified a C-to-T transition in the PKD2 gene that resulted in a change at codon 405 from gln to stop. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 POLYCYSTIC KIDNEY DISEASE 2</strong>
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PKD2, 1-BP INS, 693C
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SNP: rs1560598042,
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ClinVar: RCV000014475
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<p>By systematically screening the entire coding sequence of the PKD2 gene by SSCP analysis and heteroduplex formation in a Cypriot family with polycystic kidney disease (PKD2; 613095), Xenophontos et al. (1997) identified insertion of a cytosine in exon 2 immediately after codon 231. It caused a translation frameshift and was expected to lead to the introduction of 37 novel amino acids before the translation reached a new stop codon. This was the most N-terminal mutation reported to that time, and based on the protein's modeled structure, it was predicted to be within the first transmembrane domain. </p>
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<span class="mim-font">
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<strong>.0005 POLYCYSTIC KIDNEY DISEASE 2</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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PKD2, ARG464TER
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<br />
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SNP: rs121918042,
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ClinVar: RCV000014476, RCV001292355, RCV001659695, RCV003764572
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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>Viribay et al. (1997) identified 7 novel mutations in the PKD2 gene in patients with polycystic kidney disease (PKD2; 613095), including a C-to-T transition at nucleotide 1456 in exon 6, resulting in an arg464-to-ter substitution. </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>.0006 POLYCYSTIC KIDNEY DISEASE 2</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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PKD2, 1-BP INS, 2160A
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<br />
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SNP: rs757757289,
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gnomAD: rs757757289,
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ClinVar: RCV000014477, RCV001254204, RCV001292200, RCV001559801, RCV002513045, RCV004752706
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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>Pei et al. (1998) identified a novel mutation in the PKD2 gene in a large 4-generation family in which they had mapped polycystic kidney disease to chromosome 4 (PKD2; 613095). The mutation was a single adenosine insertion in the polyadenosine tract (nucleotides 2152-2159) of exon 11 and was predicted to result in a frameshift with premature translation termination of the PKD product, polycystin-2, immediately after codon 723. The truncated polycystin-2 was predicted to lack the calcium-binding EF-hand domain and 2 cytoplasmic domains required for the homodimerization of polycystin-2 with itself and for the heterodimerization of polycystin-2 with polycystin-1. </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 POLYCYSTIC KIDNEY DISEASE 2</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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PKD2, 1-BP INS, 197_203C
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<br />
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SNP: rs1187336837,
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ClinVar: RCV000555382, RCV000681716, RCV002289770, RCV004752949, RCV004955664
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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 7 of 21 cysts from both kidneys of a patient with polycystic kidney disease (PKD2; 613095), Koptides et al. (1999) identified a C insertion within the inherited wildtype PKD2 allele. This C insertion was different from the one previously identified (693insC; 173910.0004) in this family as the germline mutation. The insertion occurred within a sequence of 6 consecutive cytosines (nucleotides 197-203), encoding amino acids 66-68. The authors were unable to determine exactly where the insertion of the cytosine occurred. The mutation was expected to create a translation frameshift, leading to the incorporation of 22 novel amino acids before reaching a stop codon. A polymorphism at nucleotide 83, which was occupied by either G or C, encoding either arginine or proline, enabled Koptides et al. (1999) to verify that the C insertion had occurred in the inherited wildtype allele. </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 POLYCYSTIC KIDNEY DISEASE 2</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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PKD2, ASP511VAL
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<br />
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SNP: rs121918043,
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ClinVar: RCV000014479
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family with polycystic kidney disease (PKD2; 613095), Reynolds et al. (1999) identified a 1532A-T transversion in the PKD2 gene, resulting in an asp511-to-val (D511V) substitution in the predicted third transmembrane span of polycystin-2. The loss-of-function mutation demonstrated complete segregation with the disease phenotype. </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>.0009 POLYCYSTIC KIDNEY DISEASE 2</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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PKD2, 2-BP DEL/1-BP INS, NT1934
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<br />
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SNP: rs1560621750,
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ClinVar: RCV000014480
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 4-generation family with polycystic kidney disease (PKD2; 613095) that was clinically asymptomatic in the adults of the first 3 generations but manifested with perinatal death in the fourth generation, Bergmann et al. (2008) identified heterozygosity for a 2-bp deletion and 1-bp insertion (1934delACinsT) in exon 9 of the PKD2 gene, resulting in a frameshift predicted to cause premature termination. The mutation was not found in unaffected family members or in 200 ethnically matched 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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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 POLYCYSTIC KIDNEY DISEASE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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PKD2, EX3DUP
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<br />
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|
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ClinVar: RCV000033172
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|
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|
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</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 64-year-old woman with polycystic kidney disease-2 (PKD2; 613095), Bataille et al. (2011) identified a heterozygous duplication of exon 3 and the exon 3/intron boundary of the PKD2 gene, predicted to result in haploinsufficiency of PKD2. Her affected sister also carried the mutation. Family history revealed 6 additional affected family members, but they were not tested for the mutation. In addition to PKD2, the proband had situs inversus totalis, complete inversion of the thoracic large vessels, and a left-sided liver, consistent with a laterality defect. None of her 3 affected sisters had a laterality defect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<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>.0011 POLYCYSTIC KIDNEY DISEASE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
PKD2, 3-BP DUP, 305GAG
|
|
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|
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<br />
|
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|
|
SNP: rs398122932,
|
|
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|
|
|
gnomAD: rs398122932,
|
|
|
|
|
|
ClinVar: RCV000033173
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son with polycystic kidney disease-2 (PKD2; 613095), Bataille et al. (2011) identified a heterozygous 3-bp duplication (305_307dupGAG) in exon 1 of the PKD2 gene, resulting in an in-frame insertion of Glu102. The duplication was not reported in 2 large databases. Three sibs of the father were also affected, but mutation analysis was not performed. The duplication was absent in 3 unaffected children of the father. In addition to PKD2, the father had situs inversus and dextrocardia, consistent with a laterality defect. His son and affected sibs did not have laterality defects. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
|
</div>
|
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S., Ehrlich, B. E.
|
|
<strong>Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 6454-6459, 2007.
|
|
|
|
|
|
[PubMed: 17404231]
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[Full Text: https://doi.org/10.1073/pnas.0610324104]
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</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Bataille, S., Demoulin, N., Devuyst, O., Audrezet, M.-P., Dahan, K., Godin, M., Fontes, M., Pirson, Y., Burtey, S.
|
|
<strong>Association of PKD2 (polycystin 2) mutations with left-right laterality defects.</strong>
|
|
Am. J. Kidney Dis. 58: 456-460, 2011.
|
|
|
|
|
|
[PubMed: 21719175]
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|
|
[Full Text: https://doi.org/10.1053/j.ajkd.2011.05.015]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bergmann, C., Bruchle, N. O., Frank, V., Rehder, H., Zerres, K.
|
|
<strong>Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation. (Letter)</strong>
|
|
New Eng. J. Med. 359: 318-319, 2008.
|
|
|
|
|
|
[PubMed: 18635443]
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|
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[Full Text: https://doi.org/10.1056/NEJMc0801868]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Bhunia, A. K., Piontek, K., Boletta, A., Liu, L., Qian, F., Xu, P.-N., Germino, F. J., Germino, G. G.
|
|
<strong>PKD1 induces p21-waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2.</strong>
|
|
Cell 109: 157-168, 2002.
|
|
|
|
|
|
[PubMed: 12007403]
|
|
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|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(02)00716-x]
|
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Calvet, J. P.
|
|
<strong>Ciliary signaling goes down the tubes.</strong>
|
|
Nature Genet. 33: 113-114, 2003.
|
|
|
|
|
|
[PubMed: 12514736]
|
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|
|
[Full Text: https://doi.org/10.1038/ng1078]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fedeles, S. V., Tian, X., Gallagher, A.-R., Mitobe, M., Nishio, S., Lee, S. H., Cai, Y., Geng, L., Crews, C. M., Somlo, S.
|
|
<strong>A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.</strong>
|
|
Nature Genet. 43: 639-647, 2011.
|
|
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|
|
[PubMed: 21685914]
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|
|
[Full Text: https://doi.org/10.1038/ng.860]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Field, S., Riley, K.-L., Grimes, D. T., Hilton, H., Simon, M., Powles-Glover, N., Siggers, P., Bogani, D., Greenfield, A., Norris, D. P.
|
|
<strong>Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2.</strong>
|
|
Development 138: 1131-1142, 2011.
|
|
|
|
|
|
[PubMed: 21307093]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1242/dev.058149]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gallagher, A. R., Cedzich, A., Gretz, N., Somlo, S., Witzgall, R.
|
|
<strong>The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton.</strong>
|
|
Proc. Nat. Acad. Sci. 97: 4017-4022, 2000.
|
|
|
|
|
|
[PubMed: 10760273]
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|
|
[Full Text: https://doi.org/10.1073/pnas.97.8.4017]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Gao, H., Wang, Y., Wegierski, T., Skouloudaki, K., Putz, M., Fu, X., Engel, C., Boehlke, C., Peng, H., Kuehn, E. W., Kim, E., Kramer-Zucker, A., Walz, G.
|
|
<strong>PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation.</strong>
|
|
Hum. Molec. Genet. 19: 16-24, 2010.
|
|
|
|
|
|
[PubMed: 19801576]
|
|
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|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp463]
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gonzalez-Perrett, S., Kim, K., Ibarra, C., Damiano, A. E., Zotta, E., Batelli, M., Harris, P. C., Reisin, I. L., Arnaout, M. A., Cantiello, H. F.
|
|
<strong>Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca(2+)-permeable nonselective cation channel.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 1182-1187, 2001.
|
|
|
|
|
|
[PubMed: 11252306]
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|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.98.3.1182]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Grantham, J. J., Calvet, J. P.
|
|
<strong>Polycystic kidney disease: in danger of being X-rated?</strong>
|
|
Proc. Nat. Acad. Sci. 98: 790-792, 2001.
|
|
|
|
|
|
[PubMed: 11158545]
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|
|
[Full Text: https://doi.org/10.1073/pnas.98.3.790]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Grimes, D. T., Keynton, J. L., Buenavista, M. T., Jin, X., Patel, S. H., Kyosuke, S., Vibert, J., Williams, D. J., Hamada, H., Hussain, R., Nauli, S. M., Norris, D. P.
|
|
<strong>Genetic analysis reveals a hierarchy of interactions between polycystin-encoding genes and genes controlling cilia function during left-right determination.</strong>
|
|
PLoS Genet. 12: e1006070, 2016. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 27272319]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1371/journal.pgen.1006070]
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Grimm, D. H., Cai, Y., Chauvet, V., Rajendran, V., Zeltner, R., Geng, L., Avner, E. D., Sweeney, W., Somlo, S., Caplan, M. J.
|
|
<strong>Polycystin-1 distribution is modulated by polycystin-2 expression in mammalian cells.</strong>
|
|
J. Biol. Chem. 278: 36786-36793, 2003.
|
|
|
|
|
|
[PubMed: 12840011]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M306536200]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hanaoka, K., Qian, F., Boletta, A., Bhunia, A. K., Piontek, K., Tsiokas, L., Sukhatme, V. P., Guggino, W. B., Germino, G. G.
|
|
<strong>Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.</strong>
|
|
Nature 408: 990-994, 2000.
|
|
|
|
|
|
[PubMed: 11140688]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35050128]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Hayashi, T., Mochizuki, T., Reynolds, D. M., Wu, G., Cai, Y., Somlo, S.
|
|
<strong>Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2).</strong>
|
|
Genomics 44: 131-136, 1997.
|
|
|
|
|
|
[PubMed: 9286709]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1997.4851]
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|
|
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Ada Hamosh - updated : 11/20/2018<br>George E. Tiller - updated : 09/12/2017<br>Patricia A. Hartz - updated : 11/02/2016<br>Patricia A. Hartz - updated : 1/15/2014<br>Cassandra L. Kniffin - updated : 7/1/2013<br>Cassandra L. Kniffin - updated : 2/21/2013<br>Ada Hamosh - updated : 11/2/2012<br>Patricia A. Hartz - updated : 7/23/2012<br>Patricia A. Hartz - updated : 11/23/2011<br>Patricia A. Hartz - updated : 8/10/2011<br>George E. Tiller - updated : 11/12/2010<br>Patricia A. Hartz - updated : 12/10/2009<br>Patricia A. Hartz - updated : 11/12/2009<br>Matthew B. Gross - updated : 10/16/2009<br>George E. Tiller - updated : 10/14/2009<br>Patricia A. Hartz - updated : 8/15/2008<br>Marla J. F. O'Neill - updated : 7/23/2008<br>George E. Tiller - updated : 6/16/2008<br>Patricia A. Hartz - updated : 7/2/2007<br>Patricia A. Hartz - updated : 4/7/2006<br>Patricia A. Hartz - updated : 6/2/2005<br>George E. Tiller - updated : 5/5/2005<br>Patricia A. Hartz - updated : 1/6/2005<br>George E. Tiller - updated : 7/8/2003<br>Victor A. McKusick - updated : 1/13/2003<br>Victor A. McKusick - updated : 10/11/2002<br>George E. Tiller - updated : 9/6/2002<br>Patricia A. Hartz - updated : 7/1/2002<br>Patricia A. Hartz - updated : 7/1/2002<br>Stylianos E. Antonarakis - updated : 5/1/2002<br>Patricia A. Hartz - updated : 4/30/2002<br>Victor A. McKusick - updated : 7/24/2001<br>Victor A. McKusick - updated : 3/5/2001<br>Victor A. McKusick - updated : 3/1/2001<br>Ada Hamosh - updated : 12/23/2000<br>Victor A. McKusick - updated : 5/26/2000<br>Victor A. McKusick - updated : 3/7/2000<br>Victor A. McKusick - updated : 2/23/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Victor A. McKusick - updated : 12/27/1999<br>Victor A. McKusick - updated : 3/19/1999<br>Victor A. McKusick - updated : 3/11/1999<br>Victor A. McKusick - updated : 2/24/1999<br>Victor A. McKusick - updated : 7/10/1998<br>Stylianos E. Antonarakis - updated : 5/15/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 10/14/1997<br>Victor A. McKusick - updated : 9/23/1997<br>Victor A. McKusick - updated : 7/16/1997<br>Victor A. McKusick - updated : 6/23/1997<br>Victor A. McKusick - updated : 6/2/1997<br>Moyra Smith - updated : 6/6/1996
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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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