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Entry
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- *601313 - POLYCYSTIN 1; PKD1
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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">*601313</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#pathogenesis">Pathogenesis</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="#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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</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/601313">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>
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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 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=ENSG00000008710;t=ENST00000262304" 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=5310" 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=601313" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000008710;t=ENST00000262304" 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_000296,NM_001009944,XM_005255370,XM_011522528,XM_011522529,XM_011522537,XM_047434208,XM_047434209,XM_047434210,XM_047434211,XM_047434212,XM_047434213" 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_001009944" 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=601313" 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=03203&isoform_id=03203_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/PKD1" 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/790819,799335,903758,904223,3522923,62087630,62088930,119605959,119605960,119605961,225638901,225638903,225638905,292495072,530408236,696634201,758838805,767987301,767987303,767987323,1677501963,1677530014,1913472460,2217306229,2217306231,2217306235,2217306237,2217306239,2217306241,2462549290,2462549292,2462549294,2462549296,2462549298,2462549300,2462549302,2462549304,2889457791" 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/P98161" 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=5310" 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=ENSG00000008710;t=ENST00000262304" 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=PKD1" 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=PKD1" 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+5310" 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/PKD1" 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:5310" 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/5310" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000262304.9&hgg_start=2088708&hgg_end=2135898&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:9008" 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:9008" 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/pkd1" 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=601313[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=601313[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/PKD1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000008710" 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=PKD1" 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=PKD1" 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=PKD1" 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/PKD1" 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=PKD1&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/PA35521" 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:9008" 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://www.mousephenotype.org/data/genes/MGI:97603" 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/PKD1#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:97603" 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/5310/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/OMIA000807/" 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=5310" 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://zfin.org/ZDB-GENE-100707-1" 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=PKD1&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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</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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601313
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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 1; PKD1
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
PKD1 GENE<br />
|
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PBP
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PKD1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PKD1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/94?start=-3&limit=10&highlight=94">16p13.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:2088708-2135898&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:2,088,708-2,135,898</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/94?start=-3&limit=10&highlight=94">
|
|
16p13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Polycystic kidney disease 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/173900"> 173900 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
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</tr>
|
|
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|
|
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</tbody>
|
|
</table>
|
|
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<p>Polycystin-1, encoded by the PKD1 gene, forms a complex with polycystin-2 (PKD2; <a href="/entry/173910">173910</a>) that regulates multiple signaling pathways to maintain normal renal tubular structure and function (summary by <a href="#97" class="mim-tip-reference" title="Song, X., Di Giovanni, V., He, N., Wang, K., Ingram, A., Rosenblum, N. D., Pei, Y. <strong>Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks.</strong> Hum. Molec. Genet. 18: 2328-2343, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19346236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19346236</a>] [<a href="https://doi.org/10.1093/hmg/ddp165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19346236">Song et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19346236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Characterization of the PKD1 gene had been complicated by rearrangements on chromosome 16 resulting in homologous regions in 16p termed the homologous gene (HG) area. All but 3.5 kb at the 3-prime end of the PKD1 transcript (which is approximately 14 kb in total) is encoded by a region reiterated several times in the HG area. The HG region encodes 3 large transcripts of 21 kb (HG-A), 17 kb (HG-B), and 8.5 kb (HG-C), and although these have 3-prime ends that differ from PKD1, they share substantial homology to the PKD1 transcript over most of their length. It was not known, however, whether the HG transcripts produce functional proteins (summary by <a href="#38" class="mim-tip-reference" title="Hughes, J., Ward, C. J., Peral, B., Aspinwall, R., Clark, K., San Millan, J. L., Gamble, V., Harris, P. C. <strong>The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.</strong> Nature Genet. 10: 151-160, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663510</a>] [<a href="https://doi.org/10.1038/ng0695-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663510">Hughes et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7663510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To overcome cloning problems caused by the HG region, <a href="#38" class="mim-tip-reference" title="Hughes, J., Ward, C. J., Peral, B., Aspinwall, R., Clark, K., San Millan, J. L., Gamble, V., Harris, P. C. <strong>The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.</strong> Nature Genet. 10: 151-160, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663510</a>] [<a href="https://doi.org/10.1038/ng0695-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663510">Hughes et al. (1995)</a> isolated the full PKD1 gene using an exon-linking strategy. They took RNA from a cell line containing PKD1 but not the duplicate HG loci and cloned a cDNA contig of the entire PKD1 transcript. The predicted PKD1 protein, called polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The N-terminal extracellular region of over 2,500 amino acids contains leucine-rich repeats, a C-type lectin, 16 immunoglobulin-like repeats, and 4 type III fibronectin-related domains. The findings indicated that polycystin is an integral membrane protein involved in cell-cell/matrix interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7663510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 <a href="#42" class="mim-tip-reference" title="International Polycystic Kidney Disease Consortium. <strong>Polycystic kidney disease: the complete structure of the PKD1 gene and its protein.</strong> Cell 81: 289-298, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7736581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7736581</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90339-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7736581">International Polycystic Kidney Disease Consortium (1995)</a> reported the complete structure of the PKD1 gene and its protein. The PKD1 transcript contains 46 exons. The 14.5-kb PKD1 transcript encodes a 4,304-amino acid protein that has a novel domain architecture. The N-terminal half of the protein consists of a mosaic of previously described domains, including leucine-rich repeats flanked by characteristic cysteine-rich structures, LDL-A and C-type lectin domains, and 14 units of a novel 80 amino acid domain. The presence of these domains suggested that the PKD1 protein is involved in adhesive protein-protein and protein-carbohydrate interactions in the extracellular compartment. They proposed a hypothesis that links the predicted properties of the protein with the phenotypic features of autosomal dominant PKD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7736581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 study of PKD1 mRNA with an RNase protection assay, <a href="#103" class="mim-tip-reference" title="Ward, C. J., Turley, H., Ong, A. C. M., Comley, M., Biddolph, S., Chetty, R., Ratcliffe, P. J., Gatter, K., Harris, P. C. <strong>Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney.</strong> Proc. Nat. Acad. Sci. 93: 1524-1528, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8643665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8643665</a>] [<a href="https://doi.org/10.1073/pnas.93.4.1524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8643665">Ward et al. (1996)</a> found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein was assessed in kidney, using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining was restricted to epithelial cells. Expression in the developing nephron was most prominent in mature tubules, with lesser staining in Bowman capsule and the proximal ureteric bud. In later fetal and adult kidney, strong staining persisted in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. The authors suggested that the major role of polycystin is in the maintenance of renal epithelial differentiation and organization from early fetal life. Polycystin expression, monitored at the mRNA level and by immunohistochemistry, appeared higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8643665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ibraghimov-Beskrovnaya, O., Dackowski, W. R., Foggensteiner, L., Coleman, N., Thiru, S., Petry, L. R., Burn, T. C., Connors, T. D., Van Raay, T., Bradley, J., Qian, F., Onuchic, L. F., Watnick, T. J., Piontek, K., Hakim, R. M., Landes, G. M., Germino, G. G., Sandford, R., Klinger, K. W. <strong>Polycystin: in vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane-associated protein.</strong> Proc. Nat. Acad. Sci. 94: 6397-6402, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9177229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9177229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9177229[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.94.12.6397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9177229">Ibraghimov-Beskrovnaya et al. (1997)</a> assembled an authentic full-length PKD1 cDNA and demonstrated expression of polycystin in vitro. Polyclonal antibodies directed against distinct extra- and intracellular domains specifically immunoprecipitated in vitro translated polycystin. The panel of antibodies was used to determine localization of polycystin in renal epithelial and endothelial cell lines and tissues of fetal, adult, and cystic origins. In normal adult kidney and maturing fetal nephrons, polycystin expression was confined to epithelial cells of the distal nephron and vascular endothelial cells. Expression in the proximal nephron was observed only after injury-induced cell proliferation. Polycystin expression was confined to ductal epithelium in liver, pancreas, and breast, and restricted to astrocytes in normal brain. The investigators found clear evidence for the membrane localization of polycystin by both tissue sections and by confocal microscopy in cultured renal and endothelial cells. When cultured cells made cell-cell contact, polycystin was localized to the lateral membranes of cells in contact. The data suggested that polycystin probably has a widespread role in epithelial cell differentiation and maturation and in cell-cell interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9177229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 had been 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="#78" 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 the PKD2 gene product, polycystin-2 (<a href="/entry/173910">173910</a>). 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="#78" 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="#101" 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 up-regulation 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="#32" 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="#32" 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="#31" 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 endoplasmic reticulum (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 large proportion of the extracellular N terminus of polycystin-1 is composed of 15 tandemly repeated PKD repeats (<a href="#39" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Bukanov, N. O., Donohue, L. C., Dackowski, W. R., Klinger, K. W., Landes, G. M. <strong>Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1.</strong> Hum. Molec. Genet. 9: 1641-1649, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861291</a>] [<a href="https://doi.org/10.1093/hmg/9.11.1641" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861291">Ibraghimov-Beskrovnaya et al., 2000</a>). Situated between the last PKD repeat and the first transmembrane segment is the receptor for 'egg jelly' (REJ) domain, which was originally described in sea urchin. Immediately following this domain is a G protein-coupled receptor proteolytic site (GPS) domain (<a href="#19" class="mim-tip-reference" title="Delmas, P., Nomura, H., Li, X., Lakkis, M., Luo, Y., Segal, Y., Fernandez-Fernandez, J. M., Harris, P., Frischauf, A.-M., Brown, D. A., Zhou, J. <strong>Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2.</strong> J. Biol. Chem. 277: 11276-11283, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11786542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11786542</a>] [<a href="https://doi.org/10.1074/jbc.M110483200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11786542">Delmas et al., 2002</a>). <a href="#77" class="mim-tip-reference" title="Qian, F., Boletta, A., Bhunia, A. K., Xu, H., Liu, L., Ahrabi, A. K., Watnick, T. J., Zhou, F., Germino, G. G. <strong>Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations.</strong> Proc. Nat. Acad. Sci. 99: 16981-16986, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12482949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12482949</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12482949[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.252484899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12482949">Qian et al. (2002)</a> demonstrated that polycystin-1 undergoes cleavage at the GPS domain in a process that requires the REJ domain. Most of the N-terminal fragment remains tethered at the cell surface, although a small amount is secreted. PKD1-associated mutations in the REJ domain disrupt cleavage, abolish the ability of polycystin-1 to activate signal transducer and activator of transcription-1, and induce tubulogenesis in vitro. <a href="#77" class="mim-tip-reference" title="Qian, F., Boletta, A., Bhunia, A. K., Xu, H., Liu, L., Ahrabi, A. K., Watnick, T. J., Zhou, F., Germino, G. G. <strong>Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations.</strong> Proc. Nat. Acad. Sci. 99: 16981-16986, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12482949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12482949</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12482949[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.252484899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12482949">Qian et al. (2002)</a> concluded that cleavage of polycystin-1 is likely essential for its biologic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11786542+10861291+12482949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 antibodies raised against various domains of polycystin-1 and against specific adhesion complex proteins, <a href="#92" class="mim-tip-reference" title="Scheffers, M. S., van der Bent, P., Prins, F., Spruit, L., Breuning, M. H., Litvinov, S. V., de Heer, E., Peters, D. J. M. <strong>Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells.</strong> Hum. Molec. Genet. 9: 2743-2750, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063733</a>] [<a href="https://doi.org/10.1093/hmg/9.18.2743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11063733">Scheffers et al. (2000)</a> determined that polycystin-1 was detected in the cytoplasm as well as colocalizing with desmosomes of Madin-Darby canine kidney (MDCK) cells, but not with tight or adherens junctions. They further confirmed the desmosomal localization using confocal laser scanning and immunoelectron microscopy. By performing a calcium switch experiment, the authors demonstrated the sequential reassembly of tight junctions, subsequently adherens junctions, and finally desmosomes. Polycystin-1 stained the membrane only after incorporation of desmoplakin (<a href="/entry/125647">125647</a>) into the desmosomes, suggesting that membrane-bound polycystin-1 may be important for cellular signaling or cell adhesion, but not for the assembly of adhesion complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Because signaling from cell-cell and cell-matrix adhesion complexes regulates cell proliferation and polarity, <a href="#37" class="mim-tip-reference" title="Huan, Y., van Adelsberg, J. <strong>Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins.</strong> J. Clin. Invest. 104: 1459-1468, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10562308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10562308</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10562308[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI5111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10562308">Huan and van Adelsberg (1999)</a> speculated that polycystin-1 may interact with these complexes. They showed that polycystin-1 colocalizes with the cell adhesion molecules E-cadherin (CDH1; <a href="/entry/192090">192090</a>) and alpha- (<a href="/entry/116805">116805</a>), beta- (<a href="/entry/116806">116806</a>), and gamma-catenin. Polycystin-1 coprecipitated with these proteins and comigrated with them on sucrose density gradients, but it did not colocalize, coprecipitate, or comigrate with focal adhesion kinase (<a href="/entry/600758">600758</a>), a component of the focal adhesion. <a href="#37" class="mim-tip-reference" title="Huan, Y., van Adelsberg, J. <strong>Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins.</strong> J. Clin. Invest. 104: 1459-1468, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10562308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10562308</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10562308[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI5111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10562308">Huan and van Adelsberg (1999)</a> concluded that polycystin-1 is in a complex containing E-cadherin and alpha-, beta-, and gamma-catenin. These observations raised the question of whether the defects in cell proliferation and cell polarity observed in PKD are mediated by E-cadherin or the catenins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10562308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#86" class="mim-tip-reference" title="Rodova, M., Islam, M. R., Maser, R. L., Calvet, J. P. <strong>The polycystic kidney disease-1 promoter is a target of the beta-catenin/T-cell factor pathway.</strong> J. Biol. Chem. 277: 29577-29583, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12048202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12048202</a>] [<a href="https://doi.org/10.1074/jbc.M203570200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12048202">Rodova et al. (2002)</a> presented evidence for beta-catenin-induced expression of PKD1. They analyzed the promoter region of PKD1 and identified numerous transactivating factors, including 4 T-cell factor (TCF)-binding elements (TBEs). Beta-catenin induced a reporter construct containing TBE1 6-fold when cotransfected into HEK293T cells, which express TCF4 (TCF7L2; <a href="/entry/602228">602228</a>). Dominant-negative TCF4 or deletion of the TBE1 sequence inhibited the induction. Gel shift assays confirmed that TCF4 and beta-catenin could complex with the TBE1 site, and HeLa cells stably transfected with beta-catenin responded with elevated levels of endogenous PKD1 mRNA. <a href="#86" class="mim-tip-reference" title="Rodova, M., Islam, M. R., Maser, R. L., Calvet, J. P. <strong>The polycystic kidney disease-1 promoter is a target of the beta-catenin/T-cell factor pathway.</strong> J. Biol. Chem. 277: 29577-29583, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12048202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12048202</a>] [<a href="https://doi.org/10.1074/jbc.M203570200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12048202">Rodova et al. (2002)</a> concluded that the PKD1 gene is a target of the beta-catenin/TCF pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12048202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Bukanov, N. O., Donohue, L. C., Dackowski, W. R., Klinger, K. W., Landes, G. M. <strong>Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1.</strong> Hum. Molec. Genet. 9: 1641-1649, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861291</a>] [<a href="https://doi.org/10.1093/hmg/9.11.1641" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861291">Ibraghimov-Beskrovnaya et al. (2000)</a> showed that polycystin-1 is localized to cell-cell contacts in kidney epithelial cell (MDCK) cultures. In vitro binding assays demonstrated that the Ig-like domains XI to XVI form interactions with high affinity, while domains II to V interact with a lower affinity. Antibodies raised against Ig-like domains of polycystin-1 disrupted cell-cell interactions in MDCK cell monolayers. The authors hypothesized that interactions of the Ig-like repeats of polycystin-1 play an important role in mediating intercellular adhesion, and that loss of these interactions due to mutations in polycystin-1 may be an important step in cystogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Boletta, A., Qian, F., Onuchic, L. F., Bhunia, A. K., Phakdeekitcharoen, B., Hanaoka, K., Guggino, W., Monaco, L., Germino, G. G. <strong>Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells.</strong> Molec. Cell 6: 1267-1273, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106764</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00123-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106764">Boletta et al. (2000)</a> described a novel cell culture system for studying how PKD1 regulates the later stages of renal tubular differentiation. They showed that expression of human PKD1 in MDCK cells slowed their growth and protected them from programmed cell death. MDCK cells expressing PKD1 also spontaneously formed branching tubules, while control cells formed simple cysts. Increased cell proliferation and apoptosis have been implicated in the pathogenesis of cystic diseases. This study suggested that PKD1 may function to regulate both pathways, allowing cells to enter a differentiation pathway that results in tubule formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="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><a href="#111" class="mim-tip-reference" title="Xu, G. M., Sikaneta, T., Sullivan, B. M., Zhang, Q., Andreucci, M., Stehle, T., Drummond, I., Arnaout, M. A. <strong>Polycystin-1 interacts with intermediate filaments.</strong> J. Biol. Chem. 276: 46544-46552, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11581269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11581269</a>] [<a href="https://doi.org/10.1074/jbc.M107828200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11581269">Xu et al. (2001)</a> provided experimental evidence for the interaction of polycystin-1 with the intermediate filament network. They found that vimentin (<a href="/entry/193060">193060</a>) binds the C terminus of mouse polycystin-1 in a yeast 2-hybrid screen of canine kidney cells. Deletion of the coiled-coil sequence from either peptide abolished the interaction. By GST pull-down and in vitro filament assembly analyses, they also found the cytokeratins K8 (KRT8; <a href="/entry/148060">148060</a>) and K18 (KRT18; <a href="/entry/148070">148070</a>) able to bind the coiled-coil region of polycystin-1. Immunolocalization of endogenous polycystin-1 in canine kidney cells revealed discrete nodular junctional staining that overlapped staining for cytokeratin and desmoplakin (<a href="/entry/125647">125647</a>). With use of coimmunoprecipitation and cosedimentation techniques, <a href="#63" 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-1 purified from transgenic mouse kidney cells was heavily N-glycosylated, and both endoglycosidase (Endo-H)-sensitive and mature Endo-H-resistant forms of the protein were able to interact with polycystin-2. <a href="#63" 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 complex glycosylation and insertion into the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11581269+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="#12" class="mim-tip-reference" title="Bukanov, N. O., Husson, H., Dackowski, W. R., Lawrence, B. D., Clow, P. A., Roberts, B. L., Klinger, K. W., Ibraghimov-Beskrovnaya, O. <strong>Functional polycystin-1 expression is developmentally regulated during epithelial morphogenesis in vitro: downregulation and loss of membrane localization during cystogenesis.</strong> Hum. Molec. Genet. 11: 923-936, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971874</a>] [<a href="https://doi.org/10.1093/hmg/11.8.923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971874">Bukanov et al. (2002)</a> utilized a 3-dimensional MDCK in vitro model of tubulogenesis and cystogenesis to demonstrate that polycystin-1 is a novel component of desmosomal junctions of epithelial cells. Downregulation of polycystin-1 mRNA was detected in cysts as compared to tubules, leading to altered protein expression and localization. While polycystin-1 was localized to basolateral membranes of MDCK tubules, it was only detected in cytoplasmic pools in cystic cells. Polycystin-1 was not detected in intercellular contacts at early steps of tubulogenesis, but assumed its basolateral localization at the time of cell polarization and lumen formation. During a similar morphologic process, upregulation of polycystin-1 mRNA and protein levels was noted as a pancreatic ductal epithelial cell line underwent in vitro differentiation, resulting in dome formation. The authors suggested that the loss of polycystin-1 from its basolateral location in tubular epithelium may alter critical pathways controlling normal tubulogenesis leading to cystic transformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of NO. Thus, eNOS (<a href="/entry/163729">163729</a>) could have a modifier effect in ADPKD. To test this hypothesis, <a href="#73" class="mim-tip-reference" title="Persu, A., Stoenoiu, M. S., Messiaen, T., Davila, S., Robino, C., El-Khattabi, O., Mourad, M., Horie, S., Feron, O., Balligand, J.-L., Wattiez, R., Pirson, Y., Chaveau, D., Lens, X. M., Devuyst, O. <strong>Modifier effect of ENOS in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 11: 229-241, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823442</a>] [<a href="https://doi.org/10.1093/hmg/11.3.229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823442">Persu et al. (2002)</a> genotyped 173 unrelated European ADPKD patients for the glu298-to-asp (<a href="/entry/163729#0001">163729.0001</a>), intron 4 VNTR, and -786T-C (<a href="/entry/163729#0002">163729.0002</a>) polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In 93 males, the glu298-to-asp polymorphism was associated with a lower age at ESRD. This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NOS activity was decreased in renal artery samples from PKD males harboring the asp298 allele, in association with posttranslational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. <a href="#73" class="mim-tip-reference" title="Persu, A., Stoenoiu, M. S., Messiaen, T., Davila, S., Robino, C., El-Khattabi, O., Mourad, M., Horie, S., Feron, O., Balligand, J.-L., Wattiez, R., Pirson, Y., Chaveau, D., Lens, X. M., Devuyst, O. <strong>Modifier effect of ENOS in autosomal dominant polycystic kidney disease.</strong> Hum. Molec. Genet. 11: 229-241, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823442</a>] [<a href="https://doi.org/10.1093/hmg/11.3.229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823442">Persu et al. (2002)</a> concluded that glu298-to-asp is associated with a 5 year lower mean age at ESRD in a subset of ADPKD males. They hypothesized that the effect could be due to decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#61" 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="#14" 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>In mouse kidneys and MDCK cell lines, <a href="#16" class="mim-tip-reference" title="Chauvet, V., Tian, X., Husson, H., Grimm, D. H., Wang, T., Hiesberger, T., Igarashi, P., Bennett, A. M., Ibraghimov-Beskrovnaya, O., Somlo, S., Caplan, M. J. <strong>Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.</strong> J. Clin. Invest. 114: 1433-1443, 2004. Note: Erratum: J. Clin. Invest. 115: 788 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15545994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15545994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15545994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI21753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15545994">Chauvet et al. (2004)</a> demonstrated that polycystin-1 undergoes proteolytic cleavage that releases its C-terminal tail, which enters the nucleus and initiates signaling processes. Using a ureteral ligation mouse model, they showed that the cleavage occurs in vivo in association with alterations in mechanical stimuli. Polycystin-2 was observed to modulate the signaling properties of the polycystin-1 C-terminal tail. <a href="#16" class="mim-tip-reference" title="Chauvet, V., Tian, X., Husson, H., Grimm, D. H., Wang, T., Hiesberger, T., Igarashi, P., Bennett, A. M., Ibraghimov-Beskrovnaya, O., Somlo, S., Caplan, M. J. <strong>Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.</strong> J. Clin. Invest. 114: 1433-1443, 2004. Note: Erratum: J. Clin. Invest. 115: 788 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15545994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15545994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15545994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI21753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15545994">Chauvet et al. (2004)</a> concluded that this represents a pathway by which polycystin-1 transmits messages directly to the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15545994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Following its nuclear translocation in MDCK cells, <a href="#54" class="mim-tip-reference" title="Low, S. H., Vasanth, S., Larson, C. H., Mukherjee, S., Sharma, N., Kinter, M. T., Kane, M. E., Obara, T., Weimbs, T. <strong>Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.</strong> Dev. Cell 10: 57-69, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16399078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16399078</a>] [<a href="https://doi.org/10.1016/j.devcel.2005.12.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16399078">Low et al. (2006)</a> found that the C-terminal tail of human polycystin-1 interacted with Stat6 (<a href="/entry/601512">601512</a>) and P100 (<a href="/entry/602181">602181</a>) and stimulated Stat6-dependent gene expression. Under normal conditions, Stat6 localized to primary cilia of renal epithelial cells; however, cessation of apical fluid flow resulted in its nuclear translocation. Cyst-lining cells in ADPKD exhibited elevated levels of nuclear STAT6, P100, and the polycystin-1 C-terminal tail. Exogenous expression of the human polycystin-1 C-terminal tail resulted in renal cyst formation in zebrafish embryos. <a href="#54" class="mim-tip-reference" title="Low, S. H., Vasanth, S., Larson, C. H., Mukherjee, S., Sharma, N., Kinter, M. T., Kane, M. E., Obara, T., Weimbs, T. <strong>Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.</strong> Dev. Cell 10: 57-69, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16399078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16399078</a>] [<a href="https://doi.org/10.1016/j.devcel.2005.12.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16399078">Low et al. (2006)</a> concluded that upregulation of the STAT6/P100 pathway by the polycystin-1 C-terminal tail leads to the cellular changes characteristic of renal cysts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16399078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="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="#94" class="mim-tip-reference" title="Shillingford, J. M., Murcia, N. S., Larson, C. H., Low, S. H., Hedgepeth, R., Brown, N., Flask, C. A., Novick, A. C., Goldfarb, D. A., Kramer-Zucker, A., Walz, G., Piontek, K. B., Germino, G. G., Weimbs, T. <strong>The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.</strong> Proc. Nat. Acad. Sci. 103: 5466-5471, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16567633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16567633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16567633[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.0509694103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16567633">Shillingford et al. (2006)</a> found that the cytoplasmic tail of PC1 interacted with tuberin (<a href="/entry/191092">191092</a>), a regulator of MTOR (FRAP1; <a href="/entry/601231">601231</a>) kinase activity, and that the MTOR pathway was inappropriately activated in cyst-lining epithelial cells from human ADPKD patients and mouse models. Rapamycin, an inhibitor of MTOR, was effective in reducing renal cystogenesis in 2 independent mouse models of PKD, and it appeared to reduce renal cysts, at least partially, by selective induction of apoptosis and luminal shedding of cyst-lining epithelial cells. Advanced-stage ADPKD patients frequently receive a renal transplant without removal of the affected cystic kidneys, and rapamycin is often used to prevent transplant rejection. <a href="#94" class="mim-tip-reference" title="Shillingford, J. M., Murcia, N. S., Larson, C. H., Low, S. H., Hedgepeth, R., Brown, N., Flask, C. A., Novick, A. C., Goldfarb, D. A., Kramer-Zucker, A., Walz, G., Piontek, K. B., Germino, G. G., Weimbs, T. <strong>The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.</strong> Proc. Nat. Acad. Sci. 103: 5466-5471, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16567633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16567633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16567633[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.0509694103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16567633">Shillingford et al. (2006)</a> found that patients treated with rapamycin had a statistically significant reduction in native polycystic kidney size over a period of 24 months compared with patients treated with other antirejection drugs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16567633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#93" 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>
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<a href="#98" 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-PKD2 (<a href="/entry/173910">173910</a>) 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><a href="#80" class="mim-tip-reference" title="Reeders, S. T., Breuning, M. H., Davies, K. E., Nicholls, R. D., Jarman, A. P., Higgs, D. R., Pearson, P. L., Weatherall, D. J. <strong>A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16.</strong> Nature 317: 542-544, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2995836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2995836</a>] [<a href="https://doi.org/10.1038/317542a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2995836">Reeders et al. (1985)</a> showed that the PKD1 locus is closely linked to the alpha-globin locus (HBA1; <a href="/entry/141800">141800</a>) on 16p (lod = 25.85, theta = 0.05, 99% confidence limits = 2-11 cM). In establishing this linkage, they used a highly polymorphic region about 8 kb beyond the 3-prime end of the alpha-globin cluster (3-prime-HVR = 3-prime-hypervariable region). In the Oxford data (<a href="#83" class="mim-tip-reference" title="Reeders, S. T. <strong>Personal Communication.</strong> Oxford, England 10/11/1985."None>Reeders, 1985</a>), ADPKD versus phosphoglycolate phosphatase (PGP; <a href="/entry/172280">172280</a>) showed a lod score of 8.21 at theta = 0.0. PGP and HBA showed a lod score of 11.61 at theta = 0.0. In 13 South Wales kindreds, <a href="#51" class="mim-tip-reference" title="Lazarou, L. P., Davies, F., Sarfarazi, M., Coles, G. A., Harper, P. S. <strong>Adult polycystic kidney disease and linked RFLPs at the alpha-globin locus: a genetic study in the South Wales population.</strong> J. Med. Genet. 24: 466-473, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2443703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2443703</a>] [<a href="https://doi.org/10.1136/jmg.24.8.466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2443703">Lazarou et al. (1987)</a> found a maximum lod score of 24.187 at a recombination fraction of 0.03 for linkage between PKD1 and alpha-globin. Despite phenotypic heterogeneity, they found no evidence of linkage heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2995836+2443703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#108" class="mim-tip-reference" title="Watson, M. L., Wright, A. F., Macnicol, A. M., Allan, P. L., Clayton, J. F., Dempster, M., Jeremiah, S. J., Corney, G., Hopkinson, D. A. <strong>Studies of genetic linkage between adult polycystic kidney disease and three markers on chromosome 16.</strong> J. Med. Genet. 24: 457-461, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2821260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2821260</a>] [<a href="https://doi.org/10.1136/jmg.24.8.457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2821260">Watson et al. (1987)</a> found tight linkage of ADPKD and PGP; the maximum likelihood value of the recombination fraction was 0.0 with a lod score of 5.5. Together with the ADPKD versus HVR linkage data, these findings suggested to them that ADPKD and PGP are on the 5-prime side of the alpha-globin cluster. The polarity of the HBAC gene cluster viz-a-viz the centromere is unknown. The recombination fraction for the 3-prime-HVR and ADPKD is somewhat greater in males than in females (<a href="#84" class="mim-tip-reference" title="Reeders, S. T. <strong>Personal Communication.</strong> Oxford, England 1986."None>Reeders, 1986</a>)--an anomalous finding. <a href="#80" class="mim-tip-reference" title="Reeders, S. T., Breuning, M. H., Davies, K. E., Nicholls, R. D., Jarman, A. P., Higgs, D. R., Pearson, P. L., Weatherall, D. J. <strong>A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16.</strong> Nature 317: 542-544, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2995836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2995836</a>] [<a href="https://doi.org/10.1038/317542a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2995836">Reeders et al. (1985)</a> found no definite recombination between PGP and ADPKD. HBAC is distal to ADPKD but whether PGP is proximal or distal to ADPKD is unknown. The evidence on location of HBAC was conflicting, with assignments from 16p13.11 to 16p13.33. <a href="#82" class="mim-tip-reference" title="Reeders, S. T., Keith, T., Green, P., Germino, G. G., Barton, N. J., Lehmann, O. J., Brown, V. A., Phipps, P., Morgan, J., Bear, J. C., Parfrey, P. <strong>Regional localization of the autosomal dominant polycystic kidney disease locus.</strong> Genomics 3: 150-155, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2906325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2906325</a>] [<a href="https://doi.org/10.1016/0888-7543(88)90146-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2906325">Reeders et al. (1988)</a> described an array of linked markers that bracket the PKD1 locus. <a href="#26" class="mim-tip-reference" title="Germino, G. G., Barton, N. J., Lamb, J., Higgs, D. R., Harris, P., Xiao, G. H., Scherer, G., Nakamura, Y., Reeders, S. T. <strong>Identification of a locus which shows no genetic recombination with the autosomal dominant polycystic kidney disease gene on chromosome 16.</strong> Am. J. Hum. Genet. 46: 925-933, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2339691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2339691</a>]" pmid="2339691">Germino et al. (1990)</a> demonstrated a DNA marker, D16S84, that showed no recombination with PKD1 in 201 informative meioses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2995836+2339691+2906325+2821260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#75" class="mim-tip-reference" title="Pound, S. E., Carothers, A. D., Pignatelli, P. M., Macnicol, A. M., Watson, M. L., Wright, A. F. <strong>Evidence for linkage disequilibrium between D16S94 and the adult onset polycystic kidney disease (PKD1) gene.</strong> J. Med. Genet. 29: 247-248, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1583644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1583644</a>] [<a href="https://doi.org/10.1136/jmg.29.4.247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1583644">Pound et al. (1992)</a> presented evidence for linkage disequilibrium between PKD1 and D16S94. <a href="#11" class="mim-tip-reference" title="Breuning, M. H., Snijdewint, F. G. M., Brunner, H., Verwest, A., Ijdo, J. W., Saris, J. J., Dauwerse, J. G., Blonden, L., Keith, T., Callen, D. F., Hyland, V. J., Xiao, G. H., Scherer, G., Higgs, D. R., Harris, P., Bachner, L., Reeders, S. T., Germino, G., Pearson, P. L., van Ommen, G. J. B. <strong>Map of 16 polymorphic loci on the short arm of chromosome 16 close to the polycystic kidney disease gene (PKD1).</strong> J. Med. Genet. 27: 603-613, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978860</a>] [<a href="https://doi.org/10.1136/jmg.27.10.603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1978860">Breuning et al. (1990)</a> further defined the location of markers on 16p in the vicinity of the PKD1 locus. <a href="#34" class="mim-tip-reference" title="Harris, P. C., Thomas, S., Ratcliffe, P. J., Breuning, M. H., Coto, E., Lopez-Larrea, C. <strong>Rapid genetic analysis of families with polycystic kidney disease 1 by means of a microsatellite marker.</strong> Lancet 338: 1484-1487, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1683919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1683919</a>] [<a href="https://doi.org/10.1016/0140-6736(91)92300-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1683919">Harris et al. (1991)</a> identified closely linked microsatellite polymorphisms that could be used in a PCR-based assay for a rapid, inexpensive, and nonradioactive method of linkage analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1683919+1583644+1978860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Gal, A., Wirth, B., Kaariainen, H., Lucotte, G., Landais, P., Gillessen-Kaesbach, G., Muller-Wiefel, D. E., Zerres, K. <strong>Childhood manifestation of autosomal dominant polycystic kidney disease: no evidence for genetic heterogeneity.</strong> Clin. Genet. 35: 13-19, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2924430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2924430</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1989.tb02900.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2924430">Gal et al. (1989)</a> studied 10 families in which early manifestation of the disorder was a frequent finding. In all families studied, close linkage was observed between the chromosome 16 alpha-globin marker and the ADPKD locus. They concluded that there is no evidence for genetic heterogeneity of ADPKD in families with early- and later-onset disease. In 28 northern European pedigrees from England, Scotland, Holland, and eastern Finland, <a href="#81" class="mim-tip-reference" title="Reeders, S. T., Breuning, M. H., Ryynanen, M. A., Wright, A. F., Davies, K. E., King, A. W., Watson, M. L., Weatherall, D. J. <strong>A study of genetic linkage heterogeneity in adult polycystic kidney disease.</strong> Hum. Genet. 76: 348-351, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3610154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3610154</a>] [<a href="https://doi.org/10.1007/BF00272443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3610154">Reeders et al. (1987)</a> found no evidence of heterogeneity of the linkage of PKD1 with alpha-globin. (The recessive form of early-onset polycystic kidney disease is probably not linked to HBA (<a href="#84" class="mim-tip-reference" title="Reeders, S. T. <strong>Personal Communication.</strong> Oxford, England 1986."None>Reeders, 1986</a>).) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3610154+2924430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#113" class="mim-tip-reference" title="Zerres, K., Rudnik-Schoneborn, S., Deget, F., Beetz, R., Brodehl, J., Kuwertz-Broking, E., Muller-Wiefel, D., Rascher, W., Ruder, H., Scharer, K., Weber, H. P. <strong>Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk.</strong> J. Med. Genet. 30: 583-588, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8411032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8411032</a>] [<a href="https://doi.org/10.1136/jmg.30.7.583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8411032">Zerres et al. (1993)</a> also investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease (ADPKD). They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined as clinical manifestations (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. A strong familial clustering for early manifesting ADPKD was found; out of the total of 65 sibs of the 64 index patients, 15 showed comparably early manifestation. Another 10 symptom-free children were diagnosed sonographically as having ADPKD before the age of 18 years. The authors noted that high recurrence risk to sibs has important implications for genetic counseling and clinical care of affected families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8411032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Among the same 17 families reported by Bear et al. (<a href="#3" class="mim-tip-reference" title="Bear, J. C., McManamon, P., Morgan, J., Payne, R. H., Lewis, H., Gault, M. H., Churchill, D. N. <strong>Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling.</strong> Am. J. Med. Genet. 18: 45-53, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6741995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6741995</a>] [<a href="https://doi.org/10.1002/ajmg.1320180108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6741995">1984</a>, <a href="#4" class="mim-tip-reference" title="Bear, J. C., Parfrey, P. S., Morgan, J. M., Martin, C. J., Cramer, B. C. <strong>Autosomal dominant polycystic kidney disease: new information for genetic counselling.</strong> Am. J. Med. Genet. 43: 548-553, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605247</a>] [<a href="https://doi.org/10.1002/ajmg.1320430309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1605247">1992</a>), <a href="#65" class="mim-tip-reference" title="Parfrey, P. S., Bear, J. C., Morgan, J., Cramer, B. C., McManamon, P. J., Gault, M. H., Churchill, D. N., Singh, M., Hewitt, R., Somlo, S., Reeders, S. T. <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> found that polycystic kidney disease cosegregated with polymorphic DNA markers flanking the PKD1 locus in 10; in 2 families cosegregation did not occur, and in 5 families linkage could not be determined because of uninformativeness of the markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6741995+1605247+2215575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#90" class="mim-tip-reference" title="Ryynanen, M., Dolata, M. M., Lampainen, E., Reeders, S. T. <strong>Localisation of a mutation producing autosomal dominant polycystic kidney disease without renal failure.</strong> J. Med. Genet. 24: 462-465, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2443702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2443702</a>] [<a href="https://doi.org/10.1136/jmg.24.8.462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2443702">Ryynanen et al. (1987)</a> did linkage studies in a 4-generation Finnish family with polycystic kidney disease; all affected members of the extended pedigree were asymptomatic and none had developed renal failure. They showed that the mutation in this family was closely linked to the alpha-globin cluster. This might be an allelic disorder. Using DNA from a set of multigenerational families from CEPH (Centre d'etude polymorphisme humaine, Paris), <a href="#43" class="mim-tip-reference" title="Keith, T., Reeders, S. T., Brown, V. A., Green, P., Phipps, P., Bricker, A., Barton, N. J., Collier, P. S., Knowlton, R., Nelson, C., Helms, C., Donis-Keller, H. <strong>Linkage studies of autosomal dominant polycystic kidney disease (PKD1) and a genetic map of chromosome 16 based on 40 RFLP markers. (Abstract)</strong> Am. J. Hum. Genet. 41: A172, 1987."None>Keith et al. (1987)</a> constructed a genetic map of chromosome 16 based on 40 polymorphic DNA markers. The map spanned 142 cM in males, somewhat larger than the 108 cM previously estimated by chiasma counts. Males had higher recombination fractions near the alpha-globin gene cluster, but females showed higher recombination in other regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2443702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Germino, G. G., Weinstat-Saslow, D., Himmelbauer, H., Gillespie, G. A. J., Somlo, S., Wirth, B., Barton, N., Harris, K. L., Frischauf, A.-M., Reeders, S. T. <strong>The gene for autosomal dominant polycystic kidney disease lies in a 750-kb CpG-rich region.</strong> Genomics 13: 144-151, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577479</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90214-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577479">Germino et al. (1992)</a> demonstrated that the PKD1 gene lies within an extremely CpG-rich 750-kb segment of 16p13.3. Its genetic localization with respect to physically mapped markers in this segment was refined by <a href="#96" class="mim-tip-reference" title="Somlo, S., Wirth, B., Germino, G. G., Weinstat-Saslow, D., Gillespie, G. A. J., Himmelbauer, H., Steevens, L., Coucke, P., Willems, P., Bachner, L., Coto, E., Lopez-Larrea, C., Peral, B., San Millan, J. L., Saris, J. J., Breuning, M. H., Frischauf, A.-M., Reeders, S. T. <strong>Fine genetic localization of the gene for autosomal dominant polycystic kidney disease (PKD1) with respect to physically mapped markers.</strong> Genomics 13: 152-158, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349570</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90215-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1349570">Somlo et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1349570+1577479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the Spanish population, <a href="#70" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Hernandez, C., Valero, A., Lathrop, G. M., Beckmann, J. S., Moreno, F. <strong>Estimating locus heterogeneity in autosomal dominant polycystic kidney disease (ADPKD) in the Spanish population.</strong> J. Med. Genet. 30: 910-913, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7905535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7905535</a>] [<a href="https://doi.org/10.1136/jmg.30.11.910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7905535">Peral et al. (1993)</a> typed 31 families from different geographic areas using marker loci flanking PKD1 on 16p. Multilocus linkage analysis indicated that in 26 families the disease resulted from PKD1 mutations, whereas in 3 families it resulted from mutations in a locus other than PKD1; 2 other families were not informative. Using the HOMOG test, they estimated that PKD1-linked mutations were responsible for 85% of families with PKD in Spain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7905535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 400-Mb genome of the Japanese pufferfish, Fugu rubripes, is relatively free of repetitive DNA and contains genes with small introns at high density. <a href="#91" class="mim-tip-reference" title="Sandford, R., Sgotto, B., Burn, T., Brenner, S. <strong>The tuberin (TSC2), autosomal dominant polycystic kidney disease (PKD1), and somatostatin type V receptor (SSTR5) genes form a synteny group in the Fugu genome.</strong> Genomics 38: 84-86, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954784</a>] [<a href="https://doi.org/10.1006/geno.1996.0596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954784">Sandford et al. (1996)</a> demonstrated that the genes that are mutant in polycystic kidney disease-1 and tuberous sclerosis-2 (TSC2; <a href="/entry/191092">191092</a>) are conserved in the Fugu genome where they are tightly linked. In addition, sequences homologous to the SSTR5 gene (<a href="/entry/182455">182455</a>) were identified 5-prime to PKD1, defining a larger syntenic region. As in genomes of mouse and human, the Fugu TSC2 and PKD1 genes are adjacent in a tail-to-tail orientation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>PKD1 Pseudogenes</em></strong></p><p>
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A large part of the PKD1 gene is duplicated in an unknown number of homologous genes (HG) which are located on chromosome 16p13.1 and share approximately 95% homology with the PKD1 gene (<a href="#38" class="mim-tip-reference" title="Hughes, J., Ward, C. J., Peral, B., Aspinwall, R., Clark, K., San Millan, J. L., Gamble, V., Harris, P. C. <strong>The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.</strong> Nature Genet. 10: 151-160, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663510</a>] [<a href="https://doi.org/10.1038/ng0695-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663510">Hughes et al., 1995</a>). <a href="#6" class="mim-tip-reference" title="Bogdanova, N., Markoff, A., Gerke, V., McCluskey, M., Horst, J., Dworniczak, B. <strong>Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.</strong> Genomics 74: 333-341, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11414761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11414761</a>] [<a href="https://doi.org/10.1006/geno.2001.6568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11414761">Bogdanova et al. (2001)</a> examined the expression of 5 of these homologous genes located proximal to PKD1. They used RT-PCR of total RNA and mRNA associated within polysomes isolated from a human glioblastoma cell line in which polycystins are well expressed. Analysis of the products suggested that the homologs produce mRNA species with suboptimal start codons and that these mRNA species are not translated. <a href="#6" class="mim-tip-reference" title="Bogdanova, N., Markoff, A., Gerke, V., McCluskey, M., Horst, J., Dworniczak, B. <strong>Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.</strong> Genomics 74: 333-341, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11414761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11414761</a>] [<a href="https://doi.org/10.1006/geno.2001.6568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11414761">Bogdanova et al. (2001)</a> concluded that the homologs are pseudogenes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11414761+7663510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To elucidate the molecular pathways that modulate renal cyst growth in ADPKD, <a href="#97" class="mim-tip-reference" title="Song, X., Di Giovanni, V., He, N., Wang, K., Ingram, A., Rosenblum, N. D., Pei, Y. <strong>Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks.</strong> Hum. Molec. Genet. 18: 2328-2343, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19346236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19346236</a>] [<a href="https://doi.org/10.1093/hmg/ddp165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19346236">Song et al. (2009)</a> used cDNA microarray gene profiling of cysts of different size and minimally cystic tissue (MCT) from 5 PKD1 human polycystic kidneys. The authors found downregulation of kidney epithelial-restricted genes (e.g., nephron segment-specific markers and cilia-associated cystic genes such as HNF1B (<a href="/entry/189907">189907</a>), PKHD1 (<a href="/entry/606702">606702</a>), IFT88 (<a href="/entry/600595">600595</a>), and CYS1) in the PKD1 renal cysts. Upregulated genes in PKD1 cysts included those associated with renal development, mitogen-mediated proliferation, cell cycle progression, epithelial-mesenchymal transition, hypoxia, aging, and immune/inflammatory responses. The authors suggested that upregulated signaling of Wnt/beta-catenin, pleiotropic growth factors, such as VEGF (<a href="/entry/192240">192240</a>), and G protein-coupled receptors, such as PTGER2 (<a href="/entry/176804">176804</a>), was associated with renal cystic growth. By integrating these pathways with a number of dysregulated networks of transcription factors, including SRF (<a href="/entry/600589">600589</a>), <a href="#97" class="mim-tip-reference" title="Song, X., Di Giovanni, V., He, N., Wang, K., Ingram, A., Rosenblum, N. D., Pei, Y. <strong>Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks.</strong> Hum. Molec. Genet. 18: 2328-2343, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19346236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19346236</a>] [<a href="https://doi.org/10.1093/hmg/ddp165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19346236">Song et al. (2009)</a> suggested that epithelial dedifferentiation accompanied by aberrant activation and crosstalk of specific signaling pathways may be required for PKD1 cyst growth and disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19346236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#38" class="mim-tip-reference" title="Hughes, J., Ward, C. J., Peral, B., Aspinwall, R., Clark, K., San Millan, J. L., Gamble, V., Harris, P. C. <strong>The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.</strong> Nature Genet. 10: 151-160, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663510</a>] [<a href="https://doi.org/10.1038/ng0695-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663510">Hughes et al. (1995)</a> determined that the 14,148-bp PKD1 transcript is distributed among 46 exons spanning 52 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7663510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="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>). The PKD1 promoter also contains an E box, MINI (muscle initiator sequence) motif, and a binding site for AP2 (<a href="/entry/107580">107580</a>). Deletion studies of the mouse Pkd1 promoter identified a 280-bp fragment capable of driving reporter gene expression, whereas reporter constructs containing larger fragments of the promoter showed lower activity. Mutating a potential E2f-binding site within the 280-bp fragment diminished reporter activity, suggesting a role for E2F in regulating cell cycle-dependent expression of the PKD1 gene. <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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<p>The <a href="#22" class="mim-tip-reference" title="European Polycystic Kidney Disease Consortium. <strong>The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16.</strong> Cell 77: 881-894, 1994. Note: Erratum: Cell 78: 725 only, 1994. Erratum: Cell 81: page after 1170 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8004675</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90137-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8004675">European Polycystic Kidney Disease Consortium (1994)</a> isolated a gene encoding a 14-kb transcript that was disrupted by a chromosome translocation in a family with PKD1 (<a href="/entry/173900">173900</a>). Indeed, the unusual Portuguese family had both PKD and tuberous sclerosis (TSC2; <a href="/entry/191092">191092</a>), which maps to the same region of 16p. The mother had a balanced translocation, 46,XX t(16;22)(p13.3;q11.21), which was inherited by her daughter. The son, on the other hand, had an unbalanced karyotype 45,XY with monosomy for 16pter-p13.3 as well as for 22pter-q11.21. This individual had the clinical phenotype of tuberous sclerosis which was thought to be due to the fact that the TSC2 locus located within 16p13.3 was deleted in the unbalanced karyotype. The mother and the daughter with the balanced translocation had the clinical features of PKD1, while the parents of the mother were cytogenetically normal, with no clinical features of tuberous sclerosis and no renal cysts on ultrasound examination. The location of the breakpoint in the balanced translocation was more than 20 kb proximal to the TSC2 locus. The consortium isolated a gene spanning the breakpoint and designated it PBP (for 'polycystic breakpoint'). They then identified mutations in the PBP gene in other patients with PKD1. The first mutation found was a 5.5-kb genomic deletion within the 3-prime end of the PBP gene in an affected woman and in paraffin-embedded tissue from her affected father (deceased at the time of report). The second rearrangement detected was a 2-kb genomic deletion within the PBP gene which was found to have a frameshift deletion of 446 bp (between basepairs 1746 and 2192). This was a de novo mutation. Sequencing of genomic DNA in another patient demonstrated a G-to-C transition at the +1 position of the splice donor site following the 135-bp exon (<a href="#0001">601313.0001</a>). The splicing defect resulted in an in-frame deletion of 135-bp from the PBP transcript (basepairs 3696 to 3831). A fourth patient was described in which both the TSC2 gene and the PKD1 gene were deleted. Further study indicated that the deletion extended over approximately 100 kb and deleted most, if not all, of the PKD1 gene. By 'zoo blotting,' the consortium demonstrated that the PKD1 gene is conserved in other mammalian species, including horse, dog, pig, and rodents. No related sequences were seen by hybridization at normal stringency in chicken, frog, or fruit fly. <a href="#110" class="mim-tip-reference" title="Wunderle, V., Ramkissoon, Y. D., Kwok, C., Korn, R. M., King, V. E., Goodfellow, P. N. <strong>Breakpoint break for consortium studying adult polycystic kidney disease.</strong> Cell 77: 785-786, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8004666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8004666</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90123-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8004666">Wunderle et al. (1994)</a> pointed out that 3 explanations are classically used to account for dominant inheritance in a disorder such as PKD1: haploinsufficiency, gain-of-function mutations (including dominant negative effects), and 2-hit mechanisms (a second somatic mutation being required to give rise to defective cells). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8004675+8004666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Harris, P. C., Barton, N. J., Higgs, D. R., Reeders, S. T., Wilkie, A. O. M. <strong>A long-range restriction map between the alpha-globin complex and a marker closely linked to the polycystic kidney disease 1 (PKD1) locus.</strong> Genomics 7: 195-206, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2347584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2347584</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90541-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2347584">Harris et al. (1990)</a> found that the region around the PKD1 locus is unusually rich in CpG dinucleotides. In a search for the gene that is mutant in polycystic kidney disease, <a href="#29" class="mim-tip-reference" title="Gillespie, G. A. J., Somlo, S., Germino, G. G., Weinstat-Saslow, D., Reeders, S. T. <strong>CpG island in the region of an autosomal dominant polycystic kidney disease locus defines the 5-prime end of a gene encoding a putative proton channel.</strong> Proc. Nat. Acad. Sci. 88: 4289-4293, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709739</a>] [<a href="https://doi.org/10.1073/pnas.88.10.4289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709739">Gillespie et al. (1991)</a> concentrated on CpG islands in a region between 2 markers that flank the PKD1 locus and are separated by less than 750 kb. One of the genes so marked, ATP6C (<a href="/entry/108745">108745</a>), was isolated from HeLa and cultured cystic kidney epithelial cell cDNA libraries. It was found to encode a 155-amino acid peptide having 4 putative transmembrane domains. The corresponding transcript was found in all tissues tested but was most abundant in brain and kidney. The deduced amino acid sequence showed 93% similarity to part of the proton channel of vacuolar H(+)-ATPase. Because of the possible role of a mutated proton channel in the pathogenesis of cystic disease, <a href="#29" class="mim-tip-reference" title="Gillespie, G. A. J., Somlo, S., Germino, G. G., Weinstat-Saslow, D., Reeders, S. T. <strong>CpG island in the region of an autosomal dominant polycystic kidney disease locus defines the 5-prime end of a gene encoding a putative proton channel.</strong> Proc. Nat. Acad. Sci. 88: 4289-4293, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709739</a>] [<a href="https://doi.org/10.1073/pnas.88.10.4289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709739">Gillespie et al. (1991)</a> sequenced cDNAs corresponding to both alleles of an affected individual but found no differences in the deduced amino acid sequence. Moreover, transcript size and abundance were not altered in cystic kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2347584+1709739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#67" class="mim-tip-reference" title="Peral, B., Gamble, V., San Millan, J. L., Strong, C., Sloane-Stanley, J., Moreno, F., Harris, P. C. <strong>Splicing mutations of the polycystic kidney disease 1 (PKD1) gene induced by intronic deletion.</strong> Hum. Molec. Genet. 4: 569-574, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633405</a>] [<a href="https://doi.org/10.1093/hmg/4.4.569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633405">Peral et al. (1995)</a> sought mutations in the PKD1 gene in this disorder. Analysis of 3 regions in the 3-prime part of the gene revealed 2 mutations that occurred by a novel mechanism. Both were deletions (of 18 or 20 bp) within the same 75-bp intron and, although these deletions did not disrupt the splice donor or acceptor sites at the boundary of the intron, they nevertheless resulted in aberrant splicing. Two different transcripts were produced in each case; one included the normally deleted intron while the other had a 66-bp deletion due to activation of a cryptic 5-prime splice site. No normal product was generated from the deletion-mutant gene. <a href="#67" class="mim-tip-reference" title="Peral, B., Gamble, V., San Millan, J. L., Strong, C., Sloane-Stanley, J., Moreno, F., Harris, P. C. <strong>Splicing mutations of the polycystic kidney disease 1 (PKD1) gene induced by intronic deletion.</strong> Hum. Molec. Genet. 4: 569-574, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633405</a>] [<a href="https://doi.org/10.1093/hmg/4.4.569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633405">Peral et al. (1995)</a> speculated that aberrant splicing probably occurred because the deletion made the intron too small for spliceosome assembly using the authentic splice sites. They also identified a 9-bp direct repeat within the intron, which probably facilitated the intronic deletion by promoting misalignment of sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>At a point when only 7 mutations in the PKD1 gene had been described, <a href="#71" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Ong, A. C. M., Gamble, V., Ward, C. J., Strong, C., Harris, P. C. <strong>Screening the 3-prime region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.</strong> Am. J. Hum. Genet. 58: 86-96, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554072</a>]" pmid="8554072">Peral et al. (1996)</a> reported a systematic screen covering nearly 80% of the approximately 2.5 kb of translated transcript that is encoded by a single-copy DNA. They identified and characterized 6 novel mutations that, together with the previously described changes, amounted to a detection rate of 10 to 15% in the population studied. Study of the PKD1 mutation search in the PKD1 gene is complicated by the fact that most of the gene lies in a genomic region reiterated several times elsewhere on chromosome 16. The results of the study of <a href="#71" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Ong, A. C. M., Gamble, V., Ward, C. J., Strong, C., Harris, P. C. <strong>Screening the 3-prime region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.</strong> Am. J. Hum. Genet. 58: 86-96, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554072</a>]" pmid="8554072">Peral et al. (1996)</a> have important implications for genetic diagnosis of PKD1 because they indicate that most of the mutations lie within the duplicated area which is difficult to study. They provided a diagram of the structure of the polycystin protein with an indication of the site of the mutations described to date. Comparison of the phenotypes of patients with large frameshifting or terminating changes and those with more subtle in-frame changes showed no obvious differences, suggesting that they may all be inactivating changes. They cited evidence of an alternatively spliced form of PKD1 that contains an additional exon in intron 16. Inclusion of this exon would change the reading frame and result in the production of a much smaller protein product. Hence they suggested that all PKD1 mutations may be inactivating, but those in typical families disrupt just the full-length polycystin, whereas those associated with large deletions disrupt both forms of the PKD1 protein, resulting in a more severe, early-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#62" class="mim-tip-reference" title="Neophytou, P., Constantinides, R., Lazarou, A., Pierides, A., Constantinou Deltas, C. <strong>Detection of a novel nonsense mutation and an intragenic polymorphism in the PKD1 gene of a Cypriot family with autosomal dominant polycystic kidney disease.</strong> Hum. Genet. 98: 437-442, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8792818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8792818</a>] [<a href="https://doi.org/10.1007/s004390050235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8792818">Neophytou et al. (1996)</a> identified an intragenic polymorphism in the coding region of the gene. Alanine at position 4091 is encoded by either GCA or GCG. In the Cypriot population this polymorphism had a heterozygosity of 35%. <a href="#62" class="mim-tip-reference" title="Neophytou, P., Constantinides, R., Lazarou, A., Pierides, A., Constantinou Deltas, C. <strong>Detection of a novel nonsense mutation and an intragenic polymorphism in the PKD1 gene of a Cypriot family with autosomal dominant polycystic kidney disease.</strong> Hum. Genet. 98: 437-442, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8792818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8792818</a>] [<a href="https://doi.org/10.1007/s004390050235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8792818">Neophytou et al. (1996)</a> reported that this polymorphism is readily detectable with the enzyme Bsp1286I. They considered this intragenic polymorphism to be highly useful in informative families, given the instability of the PKD1 region. They also identified a 12258T-A mutation that led to premature termination of translation (<a href="#0006">601313.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8792818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#85" class="mim-tip-reference" title="Reeders, S. T. <strong>Multilocus polycystic disease.</strong> Nature Genet. 1: 235-237, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338768</a>] [<a href="https://doi.org/10.1038/ng0792-235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1338768">Reeders (1992)</a> put forward an interesting 2-hit mutational hypothesis for PKD1. He pointed out the several unusual features such as the absence of detectable abnormalities in most nephrons; even in the end-stage disease, less than 10% of the roughly 1 million nephrons in each kidney contain cysts. Furthermore, any segment of the nephron, from the glomerulus to the collecting duct, may harbor a cyst. The hypothesis suggests that at the sites of cyst formation, a somatic mutation occurs in the chromosome 16 that does not carry the inherited mutation. A prediction of the 2-hit model is that renal cysts will occasionally be found in persons without an inherited predisposition as a result of 2 somatic mutations occurring in a single cell. One or 2 renal cysts are a common radiologic finding in the general population and the probability of finding a cyst in an individual does, as predicted, rise with age. The 2-hit model predicts that the number of cysts would increase with age in PKD1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1338768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>ADPKD is characterized by progressive cyst formation in a variety of organs outside the kidney, including liver and pancreas. Using DNA from the liver cysts of 2 donors with ADPKD, <a href="#106" class="mim-tip-reference" title="Watnick, T. J., Torres, V. E., Gandolph, M. A., Qian, F., Onuchic, L. F., Klinger, K. W., Landes, G., Germino, G. G. <strong>Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease.</strong> Molec. Cell 2: 247-251, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9734362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9734362</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80135-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9734362">Watnick et al. (1998)</a> showed that intragenic, somatic mutations (frameshifts, nonsense codons, severe splicing mutations, and loss of heterozygosity) are common in hepatic cysts. All pathogenic mutations were shown to have altered the previously normal copy of the gene. These data extend the 2-hit model of cystogenesis to include a second focal manifestation of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9734362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#79" class="mim-tip-reference" title="Qian, F., Watnick, T. J., Onuchic, L. F., Germino, G. G. <strong>The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I.</strong> Cell 87: 979-987, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978603</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81793-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978603">Qian et al. (1996)</a> developed a novel method for isolating renal cystic epithelia from single cysts and showed that individual renal cysts in PKD1 are monoclonal. Loss of heterozygosity (LOH) was discovered within a subset of cysts for 2 closely linked polymorphic markers located within the PKD1 gene. Genetic analysis revealed that it was the normal haplotype that was lost. The findings provided a molecular explanation for the focal nature of cyst formation and a probable mechanism whereby mutations cause disease. The high rate at which 'second hits' must occur to account for the large number of cysts observed suggested to <a href="#79" class="mim-tip-reference" title="Qian, F., Watnick, T. J., Onuchic, L. F., Germino, G. G. <strong>The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I.</strong> Cell 87: 979-987, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978603</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81793-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978603">Qian et al. (1996)</a> that unique structural features of the PKD1 gene may be responsible for its mutability. (This is a remarkable example of the Knudson mechanism which has been established in a considerable number of neoplasms. VAM.) They previously reported an extremely unusual 2.5-kb polypyrimidine tract within intron 21 of the PKD1 gene that they postulated as being responsible for the gene's increased rate of mutation (<a href="#13" class="mim-tip-reference" title="Burn, T. C., Connors, T. D., Dackowski, W. R., Petry L. R., Van Raay, T. J., Millholland, J. M., Venet, M., Miller, G., Hakim, R. M., Landes, G. M., Klinger, K. W., Qian, F., Onuchic, L. F., Watnick, T., Germino, G. G., Doggett, N. A. <strong>Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat.</strong> Hum. Molec. Genet. 4: 575-582, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633406</a>] [<a href="https://doi.org/10.1093/hmg/4.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633406">Burn et al., 1995</a>). <a href="#79" class="mim-tip-reference" title="Qian, F., Watnick, T. J., Onuchic, L. F., Germino, G. G. <strong>The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I.</strong> Cell 87: 979-987, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978603</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81793-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978603">Qian et al. (1996)</a> postulated that the polypyrimidine tract may cause ongoing errors in its transcription-coupled repair, thus resulting in a high frequency of somatic mutation. Thus, they concluded that PKD1 is a recessive disorder, when viewed at the level of the individual renal lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7633406+8978603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mutation screening of the PKD1 gene is complicated by the large transcript size (more than 14 kb) and by reiteration of the genomic area encoding 75% of the protein on the same chromosome. The sequence similarity between the duplicated region precludes specific analysis for mutations and consequently mutations were first identified in the unique 3-prime region of PKD1. <a href="#68" class="mim-tip-reference" title="Peral, B., Gamble, V., Strong, C., Ong, A. C. M., Sloane-Stanley, J., Zerres, K., Winearls, C. G., Harris, P. C. <strong>Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.</strong> Am. J. Hum. Genet. 60: 1399-1410, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9199561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9199561</a>] [<a href="https://doi.org/10.1086/515467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9199561">Peral et al. (1997)</a> developed a novel anchored RT-PCR approach to amplify specifically duplicated regions of PKD1, employing 1 primer situated within the single-copy region and 1 within the reiterated area. This strategy was incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22 to 46; 37% of the coding region), including 11 (exons 22 to 32) within the duplicated gene region, by use of the protein-truncation test (PTT). Sixty of the patients were also screened for missense changes, by use of the nonisotopic RNase cleavage assay (NIRCA), in exons 23 to 36. In this way, <a href="#68" class="mim-tip-reference" title="Peral, B., Gamble, V., Strong, C., Ong, A. C. M., Sloane-Stanley, J., Zerres, K., Winearls, C. G., Harris, P. C. <strong>Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.</strong> Am. J. Hum. Genet. 60: 1399-1410, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9199561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9199561</a>] [<a href="https://doi.org/10.1086/515467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9199561">Peral et al. (1997)</a> identified 11 mutations, 6 within the duplicated region: 3 stop mutations, 3 frameshifting deletions of 1 nucleotide, 2 splicing defects, and 3 possible missense changes. Each mutation was detected in just 1 family, although 1 had been described previously; no mutation hotspot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggested that the mutations may inactivate the molecule. <a href="#68" class="mim-tip-reference" title="Peral, B., Gamble, V., Strong, C., Ong, A. C. M., Sloane-Stanley, J., Zerres, K., Winearls, C. G., Harris, P. C. <strong>Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.</strong> Am. J. Hum. Genet. 60: 1399-1410, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9199561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9199561</a>] [<a href="https://doi.org/10.1086/515467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9199561">Peral et al. (1997)</a> recommended RT-PCR/PTT as a rapid and efficient method to detect PKD1 mutations and differentiate pathogenic changes from polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9199561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Constantinides, R., Xenophontos, S., Neophytou, P., Nomura, S., Pierides, A., Constantinou Deltas, C. <strong>New amino acid polymorphism, Ala/Val4058, in exon 45 of the polycystic kidney disease 1 gene: evolution of alleles.</strong> Hum. Genet. 99: 644-647, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150733</a>] [<a href="https://doi.org/10.1007/s004390050421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150733">Constantinides et al. (1997)</a> reported a new amino acid polymorphism, ala/val4058, with allelic frequencies of 0.88 and 0.12, respectively, and a heterozygosity of 0.23, in the Greek and Greek-Cypriot populations. The val4058 polymorphism occurred on the background of the ala4091-G allele of the ala4091-A/G polymorphism, previously described by <a href="#62" class="mim-tip-reference" title="Neophytou, P., Constantinides, R., Lazarou, A., Pierides, A., Constantinou Deltas, C. <strong>Detection of a novel nonsense mutation and an intragenic polymorphism in the PKD1 gene of a Cypriot family with autosomal dominant polycystic kidney disease.</strong> Hum. Genet. 98: 437-442, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8792818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8792818</a>] [<a href="https://doi.org/10.1007/s004390050235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8792818">Neophytou et al. (1996)</a> and <a href="#71" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Ong, A. C. M., Gamble, V., Ward, C. J., Strong, C., Harris, P. C. <strong>Screening the 3-prime region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.</strong> Am. J. Hum. Genet. 58: 86-96, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554072</a>]" pmid="8554072">Peral et al. (1996)</a>. Neither polymorphism was observed in 44 Japanese subjects, leading <a href="#17" class="mim-tip-reference" title="Constantinides, R., Xenophontos, S., Neophytou, P., Nomura, S., Pierides, A., Constantinou Deltas, C. <strong>New amino acid polymorphism, Ala/Val4058, in exon 45 of the polycystic kidney disease 1 gene: evolution of alleles.</strong> Hum. Genet. 99: 644-647, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150733</a>] [<a href="https://doi.org/10.1007/s004390050421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150733">Constantinides et al. (1997)</a> to suggest that these polymorphic alleles would be useful for linkage analysis only in specific ethnic groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8554072+9150733+8792818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 major challenge faced by researchers attempting to do a complete mutation analysis of the PKD1 gene is the presence of several homologous loci, also located on chromosome 16. Because the sequence of PKD1 and its homologs is nearly identical in the 5-prime region of the gene, most traditional approaches to mutation analysis cannot distinguish sequence variants occurring uniquely in PKD1. Although linkage information indicates that mutations in PKD1 account for approximately 85% of all autosomal dominant PKD, relatively few mutations were identified in the 4-year period following the identification of the gene in 1994, and most were clustered in the unique portion of the gene. Approximately 70% of the length of the gene is present in at least 3 faithful copies at 16p13.1. The duplicated region extends from exon 1 to intron 34 and includes all intervening sequences. The PKD1 copies are transcribed but their respective mRNA molecules can be distinguished from authentic PKD1 transcripts on the basis of size. Furthermore, bisecting intron 21 of PKD1 is an unusual polypyrimidine tract of approximately 2.5 kb. This element is also present in the PKD1 homologs.</p><p>To study the duplicated region of PKD1, <a href="#105" class="mim-tip-reference" title="Watnick, T. J., Piontek, K. B., Cordal, T. M., Weber, H., Gandolph, M. A., Qian, F., Lens, X. M., Neumann, H. P. H., Germino, G. G. <strong>An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.</strong> Hum. Molec. Genet. 6: 1473-1481, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285784</a>] [<a href="https://doi.org/10.1093/hmg/6.9.1473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285784">Watnick et al. (1997)</a> devised a novel strategy that depends on long-range PCR and a single gene-specific primer from the unique region of the gene to amplify a PKD1-specific template that spans exons 23 to 34. This 10-kb template, amplified from genomic DNA, can be employed for mutation analysis using a wide range of sequence-based approaches. Using this long-range PCR strategy to screen for sequence variants with heteroduplex analysis, <a href="#105" class="mim-tip-reference" title="Watnick, T. J., Piontek, K. B., Cordal, T. M., Weber, H., Gandolph, M. A., Qian, F., Lens, X. M., Neumann, H. P. H., Germino, G. G. <strong>An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.</strong> Hum. Molec. Genet. 6: 1473-1481, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285784</a>] [<a href="https://doi.org/10.1093/hmg/6.9.1473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285784">Watnick et al. (1997)</a> identified several affected individuals with clusters of basepair substitutions in exons 23 and 25. In 2 patients, these changes, identified in exon 23, would be predicted to result in multiple amino acid substitutions in a short stretch of the protein. This unusual clustering of basepair substitutions suggested that mutation may result from unique structural features of the PKD1 gene. The observation that renal cysts are due to somatic mutations and the high frequency of 'second hits' implied by this in hereditary polycystic kidney disease also suggests an unusual mechanism of mutation. <a href="#105" class="mim-tip-reference" title="Watnick, T. J., Piontek, K. B., Cordal, T. M., Weber, H., Gandolph, M. A., Qian, F., Lens, X. M., Neumann, H. P. H., Germino, G. G. <strong>An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.</strong> Hum. Molec. Genet. 6: 1473-1481, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285784</a>] [<a href="https://doi.org/10.1093/hmg/6.9.1473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285784">Watnick et al. (1997)</a> observed that the PKD1 gene has 3 long polypyrimidine tracts within introns 1, 21, and 22, the longest of which is 2.5 kb in intron 21. The tract in intron 21 was the longest polypyrimidine tract sequenced to that time and contains 23 mirror repeats with stem lengths of at least 10 nucleotides. They predicted that the mirror repeats are likely to form H-DNA structures composed of a triple helix conformation under appropriate conditions. Triple helix structures can promote localized mutagenesis in cultured cells. The unusual pattern of clustered multiple basepair substitutions is consistent with that associated with triple helix formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9285784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#87" class="mim-tip-reference" title="Roelfsema, J. H., Spruit, L., Saris, J. J., Chang, P., Pirson, Y., van Ommen, G.-J. B., Peters, D. J. M., Breuning, M. H. <strong>Mutation detection in the repeated part of the PKD1 gene.</strong> Am. J. Hum. Genet. 61: 1044-1052, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345095</a>] [<a href="https://doi.org/10.1086/301600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345095">Roelfsema et al. (1997)</a> reduced the problem in mutation detection posed by the HG region by use of the protein-truncation test. They identified 8 novel mutations, 7 of which were located in the repeated part of the PKD1 gene (e.g., <a href="#0008">601313.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#105" class="mim-tip-reference" title="Watnick, T. J., Piontek, K. B., Cordal, T. M., Weber, H., Gandolph, M. A., Qian, F., Lens, X. M., Neumann, H. P. H., Germino, G. G. <strong>An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.</strong> Hum. Molec. Genet. 6: 1473-1481, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285784</a>] [<a href="https://doi.org/10.1093/hmg/6.9.1473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285784">Watnick et al. (1997)</a> devised a strategy for mutation detection in the duplicated region of PKD1. The method used 1 gene-specific primer, PKD1, as an anchor in combination with a primer from the duplicated portion to amplify PKD1-specific templates that are approximately 10 kb long and include exons 23 to 34 or exons 23 to 38. They demonstrated that the 3-prime long-range PCR product (3-prime-LR) is PKD1 specific once it has been diluted sufficiently to remove genomic contamination and could be used for nested PCR of any exon contained within it. These products could then be analyzed for PKD1 mutations with conventional methods such as heteroduplex or single-strand conformation polymorphism (SSCP) analysis. Using this technique, <a href="#105" class="mim-tip-reference" title="Watnick, T. J., Piontek, K. B., Cordal, T. M., Weber, H., Gandolph, M. A., Qian, F., Lens, X. M., Neumann, H. P. H., Germino, G. G. <strong>An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.</strong> Hum. Molec. Genet. 6: 1473-1481, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285784</a>] [<a href="https://doi.org/10.1093/hmg/6.9.1473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285784">Watnick et al. (1997)</a> identified an unusual cluster of nearly identical basepair transitions involving exon 23 in 2 unrelated individuals. These changes were predicted to result in multiple nonconservative amino acid substitutions in a short stretch of the protein. Both the unusual pattern of these mutations and their apparent independent origin prompted <a href="#104" class="mim-tip-reference" title="Watnick, T. J., Gandolph, M. A., Weber, H., Neumann, H. P. H., Germino, G. G. <strong>Gene conversion is a likely cause of mutation in PKD1.</strong> Hum. Molec. Genet. 7: 1239-1243, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668165</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668165">Watnick et al. (1998)</a> to test whether these sequence differences could have arisen through gene conversion since pseudogenes had been known to be reservoirs for mutations by this mechanism for a number of other diseases, such as Gaucher disease and congenital adrenal hyperplasia due to 21-hydroxylase deficiency (<a href="/entry/201910">201910</a>). Using changes in restriction digest patterns, they showed that these sequence substitutions were also present in a rodent-human somatic cell hybrid that contained only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. Although PKD1 and CYP21, the gene mutant in congenital adrenal hyperplasia, resemble each other in some respects, they differ in the number and proximity of their homologous loci. The PKD1 gene is replicated in at least 3 copies that are located megabases away, while CYP21 has only 1 tandemly repeated unit. Multiple adjacent nucleotide substitutions have been described in the von Willebrand factor gene (VWF; <a href="/entry/613160">613160</a>) on chromosome 12 that mimic the sequence of its pseudogene located on chromosome 22 (<a href="#20" class="mim-tip-reference" title="Eikenboom, J. C. J., Vink, T., Briet, E., Sixma, J. J., Reitsma, P. H. <strong>Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence.</strong> Proc. Nat. Acad. Sci. 91: 2221-2224, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8134377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8134377</a>] [<a href="https://doi.org/10.1073/pnas.91.6.2221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8134377">Eikenboom et al., 1994</a>). <a href="#59" class="mim-tip-reference" title="Murti, J. R., Bumbulis, M., Schimenti, J. C. <strong>Gene conversion between unlinked sequences in the germline of mice.</strong> Genetics 137: 837-843, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088528</a>] [<a href="https://doi.org/10.1093/genetics/137.3.837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088528">Murti et al. (1994)</a> demonstrated gene conversion between unlinked sequences in the germline of mice. Gene conversion, first studied extensively in yeast, is the nonreciprocal exchange of genetic information. Gene conversion and recombination may be related processes that involve pairing of homologous sequences except that in gene conversion, genetic information is transferred from the donor gene to the recipient without the donor being modified in the process. The fact that both PKD1 and its homologs contain unusual polypyrimidine tracts that are situated in adjacent introns may promote nonreciprocal recombination leading to gene conversion. They postulated that these polypyrimidine tracts form triple helices under appropriate conditions that could conceivably contribute to mutagenesis by more than 1 mechanism. Gene conversion may also account for the apparently high mutation rate, both somatic and germline, in the PKD1 gene. A high germline mutation is suggested by the frequency of polycystic kidney disease, which is estimated to be as high as 1 in 1,000 individuals, and by the high somatic mutation rate that is required, each with a separate second mutational event. It is possible, furthermore, that somatic mutation in the PKD1 gene represents the second hit in the case of the multiple cysts of PKD2 and PKD3 (<a href="#28" class="mim-tip-reference" title="Germino, G. G. <strong>Personal Communication.</strong> Baltimore, Md. 7/30/1998."None>Germino, 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9285784+8088528+9668165+8134377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#100" class="mim-tip-reference" title="Thomas, R., McConnell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. <strong>Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.</strong> Am. J. Hum. Genet. 65: 39-49, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364515</a>] [<a href="https://doi.org/10.1086/302460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364515">Thomas et al. (1999)</a> concluded that when long-range PCR is applied to identify mutations in the duplicated part of the PKD1 gene, coupled with existing mutation detection methods, virtually the whole of this large, complex gene can be screened for mutations. By means of a PKD1-specific primer in intron 1, they used an approximately 13.6-kb PCR product that includes exons 2 to 15 of the PKD1 gene to search for mutations by direct sequence analysis. This region contains the majority of the predicted extracellular domains of the PKD1 gene product, polycystin, including the 16 novel PKD domains that have similarity to immunoglobulin-like domains found in many cell adhesion molecules and cell surface receptors. In 24 unrelated patients, 7 novel mutations were found: 2 deletions (1 of 3 kb and the other of 28 bp), 1 single-base insertion, and 4 nucleotide substitutions (1 splice site, 1 nonsense, and 2 missense). Five of these mutations were predicted to cause premature termination of the protein. Two coding and 18 silent polymorphisms were also found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>It is known that several of the most severe complications of autosomal dominant polycystic kidney disease, such as intracranial aneurysms, cluster in families. <a href="#107" class="mim-tip-reference" title="Watnick, T., Phakdeekitcharoen, B., Johnson, A., Gandolph, M., Wang, M., Briefel, G., Klinger, K. W., Kimberling, W., Gabow, P., Germino, G. G. <strong>Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.</strong> Am. J. Hum. Genet. 65: 1561-1571, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577909[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/10.1086/302657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577909">Watnick et al. (1999)</a> described a cluster of 4 bp in exon 15 that is unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11 to 21 by use of long-range PCR. The 2 templates described were used to analyze 35 pedigrees selected for study because they included individuals with either intracranial aneurysms and/or very early-onset disease. <a href="#107" class="mim-tip-reference" title="Watnick, T., Phakdeekitcharoen, B., Johnson, A., Gandolph, M., Wang, M., Briefel, G., Klinger, K. W., Kimberling, W., Gabow, P., Germino, G. G. <strong>Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.</strong> Am. J. Hum. Genet. 65: 1561-1571, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577909[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/10.1086/302657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577909">Watnick et al. (1999)</a> identified 8 novel truncating mutations, 2 missense mutations not found in a panel of controls, and several informative polymorphisms. Many of the polymorphisms were also present in the homologous loci on chromosome 16, supporting the idea that they may serve as a reservoir for genetic variability in the PKD1 gene. To their surprise, <a href="#107" class="mim-tip-reference" title="Watnick, T., Phakdeekitcharoen, B., Johnson, A., Gandolph, M., Wang, M., Briefel, G., Klinger, K. W., Kimberling, W., Gabow, P., Germino, G. G. <strong>Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.</strong> Am. J. Hum. Genet. 65: 1561-1571, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577909[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/10.1086/302657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577909">Watnick et al. (1999)</a> found that 3 independently ascertained pedigrees had an identical 2-bp deletion in exon 15 (<a href="#0014">601313.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#89" class="mim-tip-reference" title="Rossetti, S., Strmecki, L., Gamble, V., Burton, S., Sneddon, V., Peral, B., Roy, S., Bakkaloglu, A., Komel, R., Winearls, C. G., Harris, P. C. <strong>Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications.</strong> Am. J. Hum. Genet. 68: 46-63, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11115377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11115377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11115377[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/10.1086/316939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11115377">Rossetti et al. (2001)</a> developed methods to amplify all of the PKD1 coding area and screened for mutations in 131 unrelated patients with ADPKD, using the protein-truncation test and direct sequencing. Mutations were identified in 57 families, and, including 24 previously characterized changes from this cohort, a detection rate of 52.3% was achieved in 155 families. Mutations were distributed through all areas of the gene, from exon 1 to exon 46, with no clear hotspot identified. There was no significant difference in mutation frequency between the single-copy and duplicated areas of the gene, but mutations were more than twice as frequent in the 3-prime half of the gene, compared with the 5-prime half. Most mutations were predicted to truncate the protein through nonsense mutations (32%), insertions or deletions (29.6%), or splicing changes (6.2%), although the figures were biased by the methods employed, and, in sequenced areas, approximately 50% of all mutations were missense or in-frame. Other studies had suggested that gene conversion may be a significant cause of mutation in PKD1, but only 3 of 69 different mutations matched the PKD1-like HG sequence. A relatively high rate of new PKD1 mutations was calculated, 1.8 x 10(-5) mutations per generation, consistent with the many different mutations identified (69 in 81 pedigrees) and suggesting significant selection against mutant alleles. In this study, the mutation detection rate of more than 50% was comparable to that achieved for other large multiexon genes and showed the feasibility of DNA diagnosis in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11115377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#72" class="mim-tip-reference" title="Perrichot, R. A., Mercier, B., Simon, P. M., Whebe, B., Cledes, J., Ferec, C. <strong>DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients.</strong> Hum. Genet. 105: 231-239, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987650</a>] [<a href="https://doi.org/10.1007/s004390051094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987650">Perrichot et al. (1999)</a> used denaturing gradient gel electrophoresis (DGGE) to scan for mutations in the nonduplicated region of the PKD1 gene in a large cohort of 146 French unrelated ADPKD patients. They identified several novel mutations: 3 frameshift mutations, 2 nonsense mutations, 2 missense mutations, 1 insertion in a frame of 9 nucleotides, 3 intronic variations, and several polymorphisms. One of these mutations, W4139X (<a href="#0015">601313.0015</a>), was said by <a href="#72" class="mim-tip-reference" title="Perrichot, R. A., Mercier, B., Simon, P. M., Whebe, B., Cledes, J., Ferec, C. <strong>DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients.</strong> Hum. Genet. 105: 231-239, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987650</a>] [<a href="https://doi.org/10.1007/s004390051094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987650">Perrichot et al. (1999)</a> to be the fourth reported de novo mutation in the PKD1 gene. Anticipation was suspected in 1 family in which the diagnosis was made in utero in a member of the most recent generation. This study was undertaken in patients in Brittany, a Celtic area in the western part of France. A previous epidemiologic study in Brittany by <a href="#95" class="mim-tip-reference" title="Simon, P., Le Goff, J.-Y., Ang, K. S., Charasse, C., Le Cacheux, P., Cam, G. <strong>Donnees epidemiologiques, cliniques et pronostiques de la maladie polykystique autosomique dominante dans une region francaise.</strong> Nephrologie 17: 123-130, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838759</a>]" pmid="8838759">Simon et al. (1996)</a> found the frequency of the disease to be close to 1 in 1,100. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8838759+10987650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="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 the PKD1 gene was of germinal nature and the mutation in the PKD2 gene was of somatic nature. The authors stated that to their knowledge this was the first demonstration of the transheterozygous model as a mechanism for human disease development. In Drosophila melanogaster, a transheterozygous situation for 2 recessive mutations, the multiple wing hair and flare-3, has been exploited by <a href="#18" class="mim-tip-reference" title="Delgado-Rodriguez, A., Ortiz-Marttelo, R., Villalobos-Pietrini, R., Gomez-Arroyo, S., Graf, U. <strong>Genotoxicity of organic extracts of airborne particles in somatic cells of Drosophila melanogaster.</strong> Chemosphere 39: 33-43, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10377966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10377966</a>] [<a href="https://doi.org/10.1016/s0045-6535(98)00586-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10377966">Delgado-Rodriguez et al. (1999)</a> for developing the wing spot test, which identifies genotoxic substances. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10377966+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="#46" class="mim-tip-reference" title="Koptides, M., Deltas, C. C. <strong>Autosomal dominant polycystic kidney disease: molecular genetics and molecular pathogenesis.</strong> Hum. Genet. 107: 115-126, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11030408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11030408</a>] [<a href="https://doi.org/10.1007/s004390000347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11030408">Koptides and Deltas (2000)</a> reviewed the molecular genetics and molecular pathogenesis of ADPKD. They reviewed data that support or possibly contradict the 2-hit hypothesis, and other data that support the transheterozygous model for cystogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11030408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 exon-by-exon SSCP analysis on long-range PCR products, <a href="#9" class="mim-tip-reference" title="Bouba, I., Koptides, M., Mean, R., Costi, C.-E., Demetriou, K., Georgiou, I., Pierides, A., Siamopoulos, K., Deltas, C. C. <strong>Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families.</strong> Europ. J. Hum. Genet. 9: 677-684, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11571556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11571556</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11571556">Bouba et al. (2001)</a> performed a systematic screening of part of the duplicated region of the PKD1 gene in a cohort of 53 Hellenic ADPKD families from Greece and Cyprus. The region screened (exons 16-34) represented 23% of the PKD1 coding sequence, and 8 probable disease mutations were identified: 5 deletions and 3 missense mutations. In one family, a 3-bp and an 8-bp deletion in exons 20 and 21, respectively, were coinherited on the same PKD1 chromosome, causing disease in the mother and 3 sons. Eleven intragenic polymorphisms were also detected, representing neutral or coding variants, confirming previous suggestions that the PKD1 gene is prone to mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11571556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#66" 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 polycystic kidney disease from independently segregating PKD1 and PKD2 mutations. Affected members who were heterozygous for mutations in both the PKD1 and PKD2 genes (transheterozygotes) had a more severe clinical course than those with mutations in only 1 of the genes. <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 17 unrelated Australian individuals with PKD1-linked autosomal dominant PKD, <a href="#58" class="mim-tip-reference" title="McCluskey, M., Schiavello, T., Hunter, M., Hantke, J., Angelicheva, D., Bogdanova, N., Markoff, A., Thomas, M., Dworniczak, B., Horst, J., Kalaydjieva, L. <strong>Mutation detection in the duplicated region of the polycystic kidney disease 1 (PKD1) gene in PKD1-linked Australian families.</strong> Hum. Mutat. 19: 240-250, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857740</a>] [<a href="https://doi.org/10.1002/humu.10045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11857740">McCluskey et al. (2002)</a> screened for disease-causing mutations in the duplicated region of the PKD1 gene. They identified 12 novel probably pathogenic DNA variants. Defects in the duplicated region of the gene accounted for 63% of the patients. Together with the previously detected mutations in the 3-prime region of the gene, the study achieved an overall mutation detection rate of 74%. They also detected 31 variants (9 novel and 22 previously published) that did not segregate with the disease and were considered to be polymorphisms. Three of the 9 novel polymorphisms were missense mutations with a predicted effect on protein conformation, emphasizing the problems of interpretation in PKD1 mutation screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Inoue, S., Inoue, K., Utsunomiya, M., Nozaki, J., Yamada, Y., Iwasa, T., Mori, E., Yoshinaga, T., Koizumi, A. <strong>Mutation analysis in PKD1 of Japanese autosomal dominant polycystic kidney disease patients.</strong> Hum. Mutat. 19: 622-628, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007219</a>] [<a href="https://doi.org/10.1002/humu.10080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007219">Inoue et al. (2002)</a> examined PKD1 mutations in Japanese ADPKD patients. Six novel chain-terminating mutations were detected. They concluded that most PKD1 mutations in Japanese ADPKD patients are novel and definitely pathogenic. One pedigree did not link to either PKD1 or PKD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Eo, H.-S., Lee, J. G., Ahn, C., Cho, J. T., Hwang, D. Y., Hwang, Y. H., Lee, E. J., Kim, Y. S., Han, J. S., Kim, S., Lee, J. S., Jeoung, D. I., Lee, S. E., Kim, U. K. <strong>Three novel mutations of the PKD1 gene in Korean patients with autosomal dominant polycystic kidney disease.</strong> Clin. Genet. 62: 169-174, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12220456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12220456</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620211.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12220456">Eo et al. (2002)</a> described 3 novel mutations of the PKD1 gene in Korean patients. In this study, the clinical data from affected individuals and from previously reported Korean PKD1 mutations showed that patients with frameshift or nonsense mutations were more prone to develop end-stage renal failure than those with missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12220456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Familial clustering of intracranial aneurysms suggests that genetic factors are important in the etiology of ADPKD. <a href="#88" class="mim-tip-reference" title="Rossetti, S., Chauveau, D., Kubly, V., Slezak, J. M., Saggar-Malik, A. K., Pei, Y., Ong, A. C. M., Stewart, F., Watson, M. L., Bergstralh, E. J., Winearls, C. G., Torres, V. E., Harris, P. C. <strong>Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype.</strong> Lancet 361: 2196-2201, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12842373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12842373</a>] [<a href="https://doi.org/10.1016/S0140-6736(03)13773-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12842373">Rossetti et al. (2003)</a> characterized mutations in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and 7 were PKD2 (12%). The median position of the PKD1 mutation was significantly further 5-prime in the vascular population than in the 87 control pedigrees (amino acid position 2163 vs 2773, p = 0.0034). Subsets of the vascular population with aneurysmal rupture, early rupture, or families with more than 1 vascular case had median mutation locations even further 5-prime. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12842373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Gout, A. M., Ravine, D., Harris, P, C., Rossetti, S., Peters, D., Breuning, M., Henske, E, P., Koizumi, A., Inoue, S., Shimizu, Y., Thongnoppakhun, W., Yenchitsomanus, P., and 23 others. <strong>Analysis of published PKD1 gene sequence variants. (Letter)</strong> Nature Genet. 39: 427-428, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17392796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17392796</a>] [<a href="https://doi.org/10.1038/ng0407-427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17392796">Gout et al. (2007)</a> retrospectively reviewed published variants in the PKD1 genes and detected errors in 39 of 771 variants (5.06%). All arose from human processing mistakes. As peer-reviewed publication is no safeguard for those considering the clinical significance of an unknown variant, the authors suggested that reporting of new variants for the proposed Human Variome Project should employ both automated reporting and expert scrutiny. Errors were grouped into 3 categories: misassignment, miscounting, and typographical. A table of erroneous variant reports with corrections was published. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17392796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Himmelbauer et al. (<a href="#36" class="mim-tip-reference" title="Himmelbauer, H., Pohlschmidt, M., Snarey, A., Somlo, S., Weinstat-Saslow, D., Germino, G., Reeders, S., Frischauf, A.-M. <strong>A syntenic region between human 16p13.3 and mouse chromosome 17. (Abstract)</strong> Cytogenet. Cell Genet. 58: 2136, 1991."None>1991</a>, <a href="#35" class="mim-tip-reference" title="Himmelbauer, H., Pohlschmidt, M., Snarey, A., Germino, G. G., Weinstat-Saslow, D., Somlo, S., Reeders, S. T., Frischauf, A.-M. <strong>Human-mouse homologies in the region of the polycystic kidney disease gene (PKD1).</strong> Genomics 13: 35-38, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349580</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90198-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1349580">1992</a>) mapped 2 human cDNA clones, derived from the region between markers flanking PKD1, in the mouse genome. From the study of recombinant inbred strains and of somatic cell hybrids, they found that the PKD1 region markers mapped to mouse chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1349580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Aziz et al. (<a href="#1" class="mim-tip-reference" title="Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B. <strong>Down-regulation of Ke6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease.</strong> Molec. Cell. Biol. 13: 1847-1853, 1993. Note: Erratum: Molec. Cell. Biol. 13: 6614 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8441417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8441417</a>] [<a href="https://doi.org/10.1128/mcb.13.3.1847-1853.1993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8441417">1993</a>, <a href="#2" class="mim-tip-reference" title="Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B. <strong>Coordinate regulation of 11-beta-HSD and Ke6 gene in cpk mouse: implications for steroid metabolic defect in PKD.</strong> Am. J. Physiol. 267: F791-F797, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7977782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7977782</a>] [<a href="https://doi.org/10.1152/ajprenal.1994.267.5.F791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7977782">1994</a>) demonstrated that the mouse Ke6 gene (<a href="/entry/601417">601417</a>) is involved in the manifestation of polycystic kidney disease in 2 different murine models of PKD. The HKE4 (<a href="/entry/601416">601416</a>) and HKE6 genes are located in the major histocompatibility complex in mouse and human, on mouse chromosome 17 and human chromosome 6, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8441417+7977782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#64" class="mim-tip-reference" title="Olsson, P. G., Lohning, C., Horsley, S., Kearney, L., Harris, P. C., Frischauf, A.-M. <strong>The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene.</strong> Genomics 34: 233-235, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661056</a>] [<a href="https://doi.org/10.1006/geno.1996.0273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661056">Olsson et al. (1996)</a> mapped the Pkd1 locus to mouse chromosome 17 using somatic cell hybrids, B x D recombinant inbred strains, and fluorescence in situ hybridization. The gene is located within a previously defined conserved synteny group that includes the mouse homolog of tuberous sclerosis-2 (TSC2; <a href="/entry/191092">191092</a>) and is linked to the alpha-globin pseudogene. Like their human counterparts, the mouse Tsc2 and Pkd1 genes are arranged in a tail-to-tail orientation with a distance of only 63 bp between the polyadenylation signals of the 2 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lohning, C., Nowicka, U., Frischauf, A.-M. <strong>The mouse homolog of PKD1: sequence analysis and alternative splicing.</strong> Mammalian Genome 8: 307-311, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9107672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9107672</a>] [<a href="https://doi.org/10.1007/s003359900429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9107672">Lohning et al. (1997)</a> studied the mouse version of the PKD1 gene. The predicted protein is 79% identical to human PKD1 and contains most of the domains identified in the human sequence. As in the human, the mouse homolog is transcribed from a unique gene and there are no transcribed, closely related copies. At the junction of exons 12 and 13, several different splicing variants were identified that lead to a predicted protein that could be secreted. These forms were found predominantly in newborn brain, while in kidney the transcript homologous to the previously described human RNA predominated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9107672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#55" class="mim-tip-reference" title="Lu, W., Peissel, B., Babakhanlou, H., Pavlova, A., Geng, L., Fan, X., Larson, C., Brent, G., Zhou, J. <strong>Perinatal lethality with kidney and pancreas defects in mice with a targeted Pkd1 mutation.</strong> Nature Genet. 17: 179-181, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326937</a>] [<a href="https://doi.org/10.1038/ng1097-179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326937">Lu et al. (1997)</a> introduced into mice by homologous recombination a Pkd1 truncation mutation that mimicked a mutation found in human ADPKD. Heterozygotes had no discernible phenotype, whereas homozygotes died during the perinatal period with massively enlarged cystic kidneys, pancreatic ductal cysts, and pulmonary hypoplasia. Renal cyst formation began at embryonic day 15.5 in proximal tubules and progressed rapidly to replace the entire renal parenchyma. The timing of cyst formation suggested that full-length polycystin is required for normal morphogenesis during elongation and maturation of tubular structures in the kidney and pancreas. Hepatic and pancreatic cysts are rather common in ADPKD (<a href="#24" class="mim-tip-reference" title="Gabow, P. A. <strong>Autosomal dominant polycystic kidney disease.</strong> New Eng. J. Med. 329: 332-342, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8321262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8321262</a>] [<a href="https://doi.org/10.1056/NEJM199307293290508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8321262">Gabow, 1993</a>), but are rarely of clinical significance. The pulmonary hypoplasia that occurred in the mice and is found in polycystic disease in childhood probably results from oligohydramnios and abdominal distention produced by renal enlargement. Although liver cysts occur in about 30% of patients with ADPKD, surprisingly none were observed in the homozygous mutant mice. There were also no abnormalities in tissues such as myocardium and vascular smooth muscle in which polycystin is normally expressed. These findings suggested that vascular abnormalities such as aneurysm may be secondary phenomena, and indeed these have been commonly attributed to the occurrence of hypertension. However, <a href="#44" class="mim-tip-reference" title="Kim, K., Drummond, I., Ibraghimov-Beskrovnaya, O., Klinger, K., Arnaout, M. A. <strong>Polycystin 1 is required for the structural integrity of blood vessels.</strong> Proc. Nat. Acad. Sci. 97: 1731-1736, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677526[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.040550097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677526">Kim et al. (2000)</a> demonstrated a primary role of PKD1 mutations in vascular fragility. They found that mouse embryos homozygous for a mutant allele, generated by knockout, exhibited subcutaneous edema, vascular leaks, and rupture of blood vessels, culminating in lethality at embryonic day 15.5. Kidney and pancreatic ductal cysts were present. They detected mouse polycystin-1 in normal endothelium and the surrounding vascular smooth muscle cells. These data revealed a requisite role for polycystin-1 in maintaining the structural integrity of the vasculature as well as epithelium and suggested that the nature of the PKD1 mutation contributes to the phenotypic variance in ADPKD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8321262+9326937+10677526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#76" class="mim-tip-reference" title="Pritchard, L., Sloane-Stanley, J. A., Sharpe, J. A., Aspinwall, R., Lu, W., Buckle, V., Strmecki, L., Walker, D., Ward, C. J., Alpers, C. E., Zhou, J., Wood, W. G., Harris, P. C. <strong>A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype.</strong> Hum. Molec. Genet. 9: 2617-2627, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063721</a>] [<a href="https://doi.org/10.1093/hmg/9.18.2617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11063721">Pritchard et al. (2000)</a> generated transgenic mice with approximately 30 copies of a 108-kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease gene, PKD1. Two such cell lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life that was markedly reduced at the conclusion of renal development. Transgenic animals from both lines often displayed multiple renal microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. To test the functionality of the transgene, animals were bred with the Pkd1del34 knockout mouse (<a href="#55" class="mim-tip-reference" title="Lu, W., Peissel, B., Babakhanlou, H., Pavlova, A., Geng, L., Fan, X., Larson, C., Brent, G., Zhou, J. <strong>Perinatal lethality with kidney and pancreas defects in mice with a targeted Pkd1 mutation.</strong> Nature Genet. 17: 179-181, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326937</a>] [<a href="https://doi.org/10.1038/ng1097-179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326937">Lu et al., 1997</a>). Both transgenic lines rescued the embryonically lethal Pkd1del34/del34 phenotype, demonstrating that human polycystin-1 can compensate for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1del34/+ animals. The authors hypothesized that overexpression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11063721+9326937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kleymenova, E., Ibraghimov-Beskrovnaya, O., Kugoh, H., Everitt, J., Xu, H., Kiguchi, K., Landes, G., Harris, P., Walker, C. <strong>Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene.</strong> Molec. Cell 7: 823-832, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11336705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11336705</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00226-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11336705">Kleymenova et al. (2001)</a> found that rats with a germline inactivation of 1 allele of the Tsc2 tumor suppressor gene developed early-onset severe bilateral polycystic kidney disease, with similarities to the human contiguous gene syndrome caused by germline codeletion of the PKD1 and TSC2 genes. Polycystic rat renal cells retained 2 normal Pkd1 alleles but were null for Tsc2 and exhibited loss of lateral membrane-localized polycystin-1. In tuberin-deficient cells, intracellular trafficking of polycystin-1 was disrupted, resulting in sequestration of polycystin-1 within the Golgi, and reexpression of Tsc2 restored correct polycystin-1 membrane localization. These data identified tuberin as a determinant of polycystin-1 functional localization and, potentially, autosomal dominant polycystic kidney disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11336705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Boulter, C., Mulroy, S., Webb, S., Fleming, S., Brindle, K., Sandford, R. <strong>Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene.</strong> Proc. Nat. Acad. Sci. 98: 12174-12179, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11593033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11593033</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11593033[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.211191098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11593033">Boulter et al. (2001)</a> described mice carrying a targeted mutation in the Pkd1 gene, which defined its expression pattern by using a lacZ reporter gene. Although heterozygous adult mice developed renal and hepatic cysts, homozygous embryos died at embryonic days 13.5 to 14.5 from a primary cardiovascular defect that included double outflow right ventricle, disorganized myocardium, and abnormal atrioventricular septation. Skeletal development was also severely compromised. These abnormalities correlated with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 was expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincided with the onset of cyst formation in transgenic mice for mutations either in Pkd1 or Pkd2, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11593033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lu, W., Shen, X., Pavlova, A., Lakkis, M., Ward, C. J., Pritchard, L., Harris, P. C., Genest, D. R., Perez-Atayde, A. R., Zhou, J. <strong>Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects.</strong> Hum. Molec. Genet. 10: 2385-2396, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11689485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11689485</a>] [<a href="https://doi.org/10.1093/hmg/10.21.2385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11689485">Lu et al. (2001)</a> reported the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a truncation mutation in Pkd1. Null homozygotes develop more aggressive renal and pancreatic cystic disease than del34/del34. Moreover, both homozygous mutants developed polyhydramnios, hydrops fetalis, spina bifida occulta, and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. The del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the 2-hit model. The authors concluded that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and polycystin-1 may be critical in both epithelium and chondrocyte development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11689485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study molecular defects in Pkd1 mutants, <a href="#60" class="mim-tip-reference" title="Muto, S., Aiba, A., Saito, Y., Nakao, K., Nakamura, K., Tomita, K., Kitamura, T., Kurabayashi, M., Nagai, R., Higashihara, E., Harris, P. C., Katsuki, M., Horie, S. <strong>Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant.</strong> Hum. Molec. Genet. 11: 1731-1742, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12095915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12095915</a>] [<a href="https://doi.org/10.1093/hmg/11.15.1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12095915">Muto et al. (2002)</a> generated a mouse with a targeted deletion of exons 2 to 6 of Pkd1. Homozygous embryos (Pkd1 -/-) developed hydrops, cardiac conotruncal defects, and renal cystogenesis. Total protein levels of beta-catenin in heart and kidney and c-myc (<a href="/entry/190080">190080</a>) in heart were decreased in Pkd1 -/- embryos. In the kidneys of Pkd1 -/-, the expression of E-cadherin and Pecam1 (<a href="/entry/173445">173445</a>) in basolateral membranes of renal tubules was attenuated, and tyrosine phosphorylation of Egfr (<a href="/entry/131550">131550</a>) and Gab1 (<a href="/entry/604439">604439</a>) were constitutively enhanced when cystogenesis started on embryonic day 15.5 to 16.5. Maternally administered pioglitazone, a thiazolidinedione compound, resolved these molecular defects of Pkd1 -/-. Treatment with pioglitazone improved survival of Pkd1 -/- embryos and ameliorated the cardiac defects and the degree of renal cystogenesis. Long-term treatment with pioglitazone improved the endothelial function of adult Pkd1 +/-. The authors concluded that molecular defects observed in Pkd1 -/- embryos contributed to the pathogenesis of ADPKD, and that thiazolidinediones had a compensatory effect on the pathway affected by the loss of polycystin-1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12095915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#109" 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 suggested 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><a href="#49" class="mim-tip-reference" title="Lantinga-van Leeuwen, I. S., Dauwerse, J. G., Baelde, H. J., Leonhard, W. N., van de Wal, A., Ward, C. J., Verbeek, S., DeRuiter, M. C., Breuning, M. H., de Heer, E., Peters, D. J. M. <strong>Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.</strong> Hum. Molec. Genet. 13: 3069-3077, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15496422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15496422</a>] [<a href="https://doi.org/10.1093/hmg/ddh336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15496422">Lantinga-van Leeuwen et al. (2004)</a> generated mice carrying a hypomorphic Pkd1 allele (Pkd1nl), which yielded only 13 to 20% normally spliced Pkd1 transcripts in homozygous mice. Homozygous Pkd1nl mice were viable, showing bilaterally enlarged polycystic kidneys. In addition, homozygous Pkd1nl mice showed dilatations of pancreatic and liver bile ducts as well as cardiovascular abnormalities, pathogenic features similar to the human ADPKD phenotype. The authors concluded that a reduced dosage of Pkd1 is sufficient to initiate cystogenesis and vascular defects, and that low Pkd1 gene expression levels can overcome the embryonic lethality seen in Pkd1-knockout mice. <a href="#49" class="mim-tip-reference" title="Lantinga-van Leeuwen, I. S., Dauwerse, J. G., Baelde, H. J., Leonhard, W. N., van de Wal, A., Ward, C. J., Verbeek, S., DeRuiter, M. C., Breuning, M. H., de Heer, E., Peters, D. J. M. <strong>Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.</strong> Hum. Molec. Genet. 13: 3069-3077, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15496422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15496422</a>] [<a href="https://doi.org/10.1093/hmg/ddh336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15496422">Lantinga-van Leeuwen et al. (2004)</a> hypothesized that in patients, reduced PKD1 expression of the normal allele below a critical level, due to genetic, environmental, or stochastic factors, may lead to cyst formation in the kidneys and other clinical features of ADPKD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15496422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 homolog of the human PKD1 gene maps to feline chromosome E3. <a href="#112" class="mim-tip-reference" title="Young, A. E., Biller, D. S., Herrgesell, E. J., Roberts, H. R., Lyons, L. A. <strong>Feline polycystic kidney disease is linked to the PKD1 region.</strong> Mammalian Genome 16: 59-65, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674734</a>] [<a href="https://doi.org/10.1007/s00335-004-2412-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15674734">Young et al. (2005)</a> demonstrated that the feline polycystic kidney disease maps to this region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15674734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#74" class="mim-tip-reference" title="Piontek, K., Menezes, L. F., Garcia-Gonzalez, M. A., Huso, D. L., Germino, G. G. <strong>A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1.</strong> Nature Med. 13: 1490-1495, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17965720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17965720</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17965720[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/nm1675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17965720">Piontek et al. (2007)</a> found that inactivation of the Pkd1 gene in mice before postnatal day 13 resulted in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 or later resulted in cysts only after 5 months. In both cases, the cysts originated from all tubular segments. The abrupt change in response to Pkd1 inactivation corresponded to a brake point in renal growth and significant changes in gene expression. <a href="#74" class="mim-tip-reference" title="Piontek, K., Menezes, L. F., Garcia-Gonzalez, M. A., Huso, D. L., Germino, G. G. <strong>A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1.</strong> Nature Med. 13: 1490-1495, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17965720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17965720</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17965720[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/nm1675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17965720">Piontek et al. (2007)</a> concluded that the pathologic consequences of PKD1 inactivation are defined by a developmental switch that signals terminal renal maturation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17965720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Patients with tuberous sclerosis often develop renal cysts and those with inherited codeletions of PKD1 gene develop severe, early-onset polycystic kidneys. Using mouse models, <a href="#8" class="mim-tip-reference" title="Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P. <strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong> Hum. Molec. Genet. 18: 2166-2176, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19321600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19321600</a>] [<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19321600">Bonnet et al. (2009)</a> showed that many of the earliest lesions from Tsc1 (<a href="/entry/605284">605284</a>) +/-, Tsc2 +/-, and Pkd1 +/- mice did not exhibit activation of mTOR, confirming an mTOR-independent pathway of renal cystogenesis. Using Tsc1/Pkd1 and Tsc2/Pkd1 heterozygous double-mutants, the authors showed functional cooperation and an effect on renal primary cilium length between hamartin and tuberin with polycystin-1. The Tsc1, Tsc2, and Pkd1 gene products helped regulate primary cilia length in renal tubules, renal epithelial cells, and precystic hepatic cholangiocytes. Consistent with the function of cilia in modulating cell polarity, <a href="#8" class="mim-tip-reference" title="Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P. <strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong> Hum. Molec. Genet. 18: 2166-2176, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19321600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19321600</a>] [<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19321600">Bonnet et al. (2009)</a> found that many dividing precystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2, and Pkd1 heterozygous mice were highly misoriented. <a href="#8" class="mim-tip-reference" title="Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P. <strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong> Hum. Molec. Genet. 18: 2166-2176, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19321600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19321600</a>] [<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19321600">Bonnet et al. (2009)</a> proposed that defects in cell polarity may underlie cystic disease associated with TSC1, TSC2, and PKD1, and that targeting of this pathway may be of key therapeutic benefit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19321600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#99" class="mim-tip-reference" title="Takakura, A., Contrino, L., Zhou, X., Bonventre, J. V., Sun, Y., Humphreys, B. D., Zhou, J. <strong>Renal injury is a third hit promoting rapid development of adult polycystic kidney disease.</strong> Hum. Molec. Genet. 18: 2523-2531, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19342421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19342421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19342421[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/ddp147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19342421">Takakura et al. (2009)</a> showed that renal injury led to massive cystic disease in a mouse model of adult inactivation of Pkd1 using the Mx1Cre(+) allele. Cysts were labeled with a collecting duct/tubule marker Dolichos biflorus agglutinin, which correlated with the site of Cre-mediated recombination in the collecting system. BrdU labeling revealed that cyst-lining epithelial cells were composed of regenerated cells in response to renal injury. <a href="#99" class="mim-tip-reference" title="Takakura, A., Contrino, L., Zhou, X., Bonventre, J. V., Sun, Y., Humphreys, B. D., Zhou, J. <strong>Renal injury is a third hit promoting rapid development of adult polycystic kidney disease.</strong> Hum. Molec. Genet. 18: 2523-2531, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19342421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19342421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19342421[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/ddp147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19342421">Takakura et al. (2009)</a> proposed a role for polycystin-1 in kidney injury and repair and suggested that renal injury may constitute a 'third hit' resulting in rapid cyst formation in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19342421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kurbegovic, A., Cote, O., Couillard, M., Ward, C. J., Harris, P. C., Trudel, M. <strong>Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes.</strong> Hum. Molec. Genet. 19: 1174-1189, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20053665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20053665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20053665[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/ddp588" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20053665">Kurbegovic et al. (2010)</a> generated 3 transgenic mouse lines from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wildtype genomic Pkd1 expression within the native tissue and temporal regulation. The mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from 2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Pkd1(TAG) mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis, as is frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and approximately 15% intrahepatic cysts of the bile ducts, affecting females preferentially. A significant proportion of mice developed cardiac anomalies with severe left ventricular hypertrophy, marked aortic arch distention, and/or valvular stenosis and calcification that had profound functional impact. Pkd1(TAG) mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20053665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 (PCLD1, <a href="/entry/174050">174050</a>; PCLD2, <a href="/entry/617004">617004</a>), Prkcsh (<a href="/entry/177060">177060</a>) and Sec63 (<a href="/entry/608648">608648</a>), respectively, and 3 genes mutated in polycystic kidney disease, Pkd1, Pkd2, and Pkhd1, <a href="#23" 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="#23" 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="#57" 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="#57" 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 (<a href="/entry/604683">604683</a>) 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="#57" 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, 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><a href="#15" class="mim-tip-reference" title="Chanmugam, D., Rasaretnam, R., Karunaratne, K. E. S. <strong>Hereditary spherocytosis and polycystic disease of the kidneys in four members of a family.</strong> Am. J. Hum. Genet. 23: 66, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5581983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5581983</a>]" pmid="5581983">Chanmugam et al. (1971)</a> reported a family that might suggest linkage of hereditary spherocytosis (see <a href="/entry/182900">182900</a>) and polycystic kidney disease. A father and 3 children had both diseases. Three other children and 4 sibs of the father were thought to be free of both diseases. There is, however, no other suggestion of location of a spherocytosis locus on chromosome 16, or chromosome 4 (cf. <a href="/entry/173910">173910</a>), where genes for adult polycystic kidney disease have been mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5581983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 probands with polycystic kidney disease-1 (PKD1; <a href="/entry/173900">173900</a>), the <a href="#22" class="mim-tip-reference" title="European Polycystic Kidney Disease Consortium. <strong>The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16.</strong> Cell 77: 881-894, 1994. Note: Erratum: Cell 78: 725 only, 1994. Erratum: Cell 81: page after 1170 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8004675</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90137-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8004675">European Polycystic Kidney Disease Consortium (1994)</a> found 4 mutations in the PKD1 gene, including a G-to-C transition at position +1 of the splice donor site following the 135-bp exon and resulting in an in-frame deletion of basepairs 3696-3831. The proband was from a large family in which the disease could be traced through 3 generations. In a parent and 2 affected sibs, the abnormal transcript segregated with PKD1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8004675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs199476094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476094;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=rs199476094" 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=rs199476094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#102" class="mim-tip-reference" title="Turco, A. E., Rossetti, S., Bresin, E., Corra, S., Gammaro, L., Maschio, G., Pignatti, P. F. <strong>A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family.</strong> Hum. Molec. Genet. 4: 1331-1335, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581371</a>] [<a href="https://doi.org/10.1093/hmg/4.8.1331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581371">Turco et al. (1995)</a> used PCR with primer pairs located in the 3-prime unique region of the PKD1 gene and heteroduplex DNA analysis in 20 unrelated ADPKD probands (PKD1; <a href="/entry/173900">173900</a>) from northern Italy, all of whom were members of families in which previous studies had indicated linkage to PKD1. In 5 affected individuals from the same family, they found novel aberrant bands that were absent in 13 unaffected family members. Cloning and automated DNA sequencing revealed a C-to-T transition at nucleotide 3817 of the published cDNA sequence, which created a premature stop codon. The mutation changed a CAG codon for glutamine to a TAG amber stop codon (Q1273X). The mutation destroyed an MspA1I restriction site, and the abnormal restriction pattern was observed on genomic DNA from all the affected family members. RT-PCR and restriction analysis performed on peripheral white blood cell mRNA showed that in the affected members both the mutant and the normal transcript were represented. The mutation was not found in the probands of the other families studied. This appears to have been the first nonsense mutation described in the PKD1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1567154953 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567154953;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=rs1567154953" 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=rs1567154953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Among the 6 novel mutations in families with polycystic kidney disease (PDK1; <a href="/entry/173900">173900</a>) identified by <a href="#71" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Ong, A. C. M., Gamble, V., Ward, C. J., Strong, C., Harris, P. C. <strong>Screening the 3-prime region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.</strong> Am. J. Hum. Genet. 58: 86-96, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554072</a>]" pmid="8554072">Peral et al. (1996)</a> was an in-frame 15-bp deletion that removed 5 amino acids, RQVRL, between amino acids 3747 and 3753. The deletion was probably promoted by misalignment of 2 directly repeated 7-bp sequences. The repeated sequences meant that the precise region deleted could not be determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs199476095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476095;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/rs199476095?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=rs199476095" 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=rs199476095" 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=RCV000008681 OR RCV000788852" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008681, RCV000788852" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008681...</a>
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<p><a href="#71" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Ong, A. C. M., Gamble, V., Ward, C. J., Strong, C., Harris, P. C. <strong>Screening the 3-prime region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.</strong> Am. J. Hum. Genet. 58: 86-96, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554072</a>]" pmid="8554072">Peral et al. (1996)</a> found an abnormal fragment by SSCP analysis of the PKD1 gene in a patient with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>). Direct sequencing revealed a C-to-T transition changing the arg4227 codon, CGA, to a stop codon, TGA, and giving rise to a predicted truncated protein 76 amino acids shorter than the normal protein. The same abnormality was found in 2 affected relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1</strong>
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PKD1, GLN3837TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476096 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476096;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=rs199476096" 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=rs199476096" 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=RCV000008682 OR RCV002293410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008682, RCV002293410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008682...</a>
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<p><a href="#71" class="mim-tip-reference" title="Peral, B., San Millan, J. L., Ong, A. C. M., Gamble, V., Ward, C. J., Strong, C., Harris, P. C. <strong>Screening the 3-prime region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.</strong> Am. J. Hum. Genet. 58: 86-96, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554072</a>]" pmid="8554072">Peral et al. (1996)</a> used SSCP analysis followed by direct sequencing in a patient with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>) revealed a gln3837-to-ter (CAG-to-TAG, Q3837X) mutation in the PKD1 gene. The mutation abolished a PvuII restriction site and this was used to confirm the mutation in 2 other affected relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, CYS4086TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476097 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476097;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=rs199476097" 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=rs199476097" 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=RCV000008683" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008683" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008683</a>
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<p>In a large Cypriot family with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>), <a href="#62" class="mim-tip-reference" title="Neophytou, P., Constantinides, R., Lazarou, A., Pierides, A., Constantinou Deltas, C. <strong>Detection of a novel nonsense mutation and an intragenic polymorphism in the PKD1 gene of a Cypriot family with autosomal dominant polycystic kidney disease.</strong> Hum. Genet. 98: 437-442, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8792818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8792818</a>] [<a href="https://doi.org/10.1007/s004390050235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8792818">Neophytou et al. (1996)</a> identified a T-to-A nucleotide substitution at position 12258 in the 3-prime region of the PKD1 gene that led to a cys4086-to-ter mutation (C4086X). The premature stop codon is expected to remove 217 amino acids from the C-terminal intracellular domain of the gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8792818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, TYR3818TER
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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> rs199476098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476098;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/rs199476098?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=rs199476098" 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=rs199476098" 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=RCV000008684 OR RCV003993740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008684, RCV003993740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008684...</a>
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<p><a href="#69" class="mim-tip-reference" title="Peral, B., Ong, A. C. M., San Millan, J. L., Gamble, V., Rees, L., Harris, P. C. <strong>A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1).</strong> Hum. Molec. Genet. 5: 539-542, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8845849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8845849</a>] [<a href="https://doi.org/10.1093/hmg/5.4.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8845849">Peral et al. (1996)</a> described a tyr3818-to-ter (Y3818X) mutation in the PKD1 gene in a severely affected child with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>). They found the same mutation in her clinically normal twin brother and in her father who had typical adult-onset disease. Because the same stable mutation was associated with very different disease severity in this family, <a href="#69" class="mim-tip-reference" title="Peral, B., Ong, A. C. M., San Millan, J. L., Gamble, V., Rees, L., Harris, P. C. <strong>A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1).</strong> Hum. Molec. Genet. 5: 539-542, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8845849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8845849</a>] [<a href="https://doi.org/10.1093/hmg/5.4.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8845849">Peral et al. (1996)</a> proposed that a small number of modifying factors may radically affect the course of type 1 polycystic kidney disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8845849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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PKD1, 12036G-A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1218054241 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1218054241;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/rs1218054241?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=rs1218054241" 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=rs1218054241" 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=RCV000008685 OR RCV003162219" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008685, RCV003162219" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008685...</a>
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<p>In individuals of Dutch origin with autosomal dominant polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>), <a href="#87" class="mim-tip-reference" title="Roelfsema, J. H., Spruit, L., Saris, J. J., Chang, P., Pirson, Y., van Ommen, G.-J. B., Peters, D. J. M., Breuning, M. H. <strong>Mutation detection in the repeated part of the PKD1 gene.</strong> Am. J. Hum. Genet. 61: 1044-1052, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345095</a>] [<a href="https://doi.org/10.1086/301600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345095">Roelfsema et al. (1997)</a> used the protein truncation test (PTT) to detect mutations in the PKD1 gene. Since the PTT detects only translation-terminating mutations, all mutations that they found were either base substitutions leading to a stop codon or frameshifts. In 4 cases there were small deletions leading to frameshifts; base substitutions were found in 3 individuals. One of these was a G-to-A transition of nucleotide 12036 in exon 44. The transition created a new Sau3AI restriction site and eliminated an AvaII site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567192790 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567192790;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=rs1567192790" 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=rs1567192790" 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=RCV000008686" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008686" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008686</a>
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<p>Using long-range PCR and direct sequence analysis in a group of 24 unrelated patients with autosomal dominant polycystic kidney disease (<a href="/entry/173900">173900</a>), <a href="#100" class="mim-tip-reference" title="Thomas, R., McConnell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. <strong>Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.</strong> Am. J. Hum. Genet. 65: 39-49, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364515</a>] [<a href="https://doi.org/10.1086/302460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364515">Thomas et al. (1999)</a> identified 7 novel mutations in the PKD1 gene, one of which was a 28-bp deletion involving nucleotides 6434-6461 in exon 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, IVS14AS, G-A, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567204631 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567204631;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=rs1567204631" 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=rs1567204631" 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=RCV000008687" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008687" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008687</a>
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<p>One of 7 unique mutations identified by <a href="#100" class="mim-tip-reference" title="Thomas, R., McConnell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. <strong>Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.</strong> Am. J. Hum. Genet. 65: 39-49, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364515</a>] [<a href="https://doi.org/10.1086/302460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364515">Thomas et al. (1999)</a> in patients with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>) was a splice mutation, a G-to-A transition at position -1 in the acceptor site in intron 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1</strong>
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PKD1, ARG324LEU
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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> rs199476099 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476099;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/rs199476099?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=rs199476099" 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=rs199476099" 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=RCV000008688 OR RCV000756490 OR RCV001292035 OR RCV003150927 OR RCV003924816" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008688, RCV000756490, RCV001292035, RCV003150927, RCV003924816" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008688...</a>
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<p>One of 7 unique mutations identified by <a href="#100" class="mim-tip-reference" title="Thomas, R., McConnell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. <strong>Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.</strong> Am. J. Hum. Genet. 65: 39-49, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364515</a>] [<a href="https://doi.org/10.1086/302460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364515">Thomas et al. (1999)</a> by long-range PCR and direct sequencing of the PKD1 gene in patients with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>) was an arg324-to-leu (R324L) mutation in exon 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<strong>.0012 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, LEU845SER
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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> rs199476100 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476100;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/rs199476100?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=rs199476100" 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=rs199476100" 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=RCV000008689 OR RCV000712602 OR RCV000761309 OR RCV001292482 OR RCV004739297" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008689, RCV000712602, RCV000761309, RCV001292482, RCV004739297" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008689...</a>
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<p>One of 7 unique mutations identified by <a href="#100" class="mim-tip-reference" title="Thomas, R., McConnell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. <strong>Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.</strong> Am. J. Hum. Genet. 65: 39-49, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364515</a>] [<a href="https://doi.org/10.1086/302460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364515">Thomas et al. (1999)</a> by long-range PCR and direct sequencing of the PKD1 gene in patients with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>) was a leu845-to-ser (L845S) mutation in exon 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, GLN1922TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476101 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476101;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=rs199476101" 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=rs199476101" 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=RCV000008690" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008690" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008690</a>
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<p>One of 7 unique mutations identified by <a href="#100" class="mim-tip-reference" title="Thomas, R., McConnell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. <strong>Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.</strong> Am. J. Hum. Genet. 65: 39-49, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364515</a>] [<a href="https://doi.org/10.1086/302460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364515">Thomas et al. (1999)</a> by long-range PCR and direct sequencing of the PKD1 gene in patients with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>) was a nonsense mutation, gln1922 to ter (Q1922X), in exon 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0014" class="mim-anchor"></a>
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<strong>.0014 POLYCYSTIC KIDNEY DISEASE 1, SEVERE</strong>
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PKD1, 2-BP DEL, 5224AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555455457 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555455457;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=rs1555455457" 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=rs1555455457" 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=RCV000518367 OR RCV000989457 OR RCV001292374 OR RCV001813786 OR RCV004023518 OR RCV004740299" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000518367, RCV000989457, RCV001292374, RCV001813786, RCV004023518, RCV004740299" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000518367...</a>
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<p>In 3 of 35 independently ascertained pedigrees with polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>) selected for study because they included individuals with either intracranial aneurysms and/or very early-onset disease, <a href="#107" class="mim-tip-reference" title="Watnick, T., Phakdeekitcharoen, B., Johnson, A., Gandolph, M., Wang, M., Briefel, G., Klinger, K. W., Kimberling, W., Gabow, P., Germino, G. G. <strong>Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.</strong> Am. J. Hum. Genet. 65: 1561-1571, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577909[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/10.1086/302657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577909">Watnick et al. (1999)</a> identified an identical 2-bp deletion (AG) at nucleotide 5224 in exon 15 of the PKD1 gene. One family contained an individual with a cerebral aneurysm. A second family was evaluated because a child had very early-onset disease; the affected father had the same mutation as the daughter. The third family had at least 3 individuals with aneurysms, including 1 with very early onset. There were 2 additional individuals in this family (both cousins of the individual with both early onset-disease and aneurysm) who had very early-onset disease but from whom DNA samples were not available. Although each of these 3 families had individuals who were severely affected, there were also individuals with renal cystic disease and a more routine presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0015 POLYCYSTIC KIDNEY DISEASE 1, SEVERE</strong>
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PKD1, TRP4139TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476102 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476102;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=rs199476102" 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=rs199476102" 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=RCV000008692 OR RCV004783721" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008692, RCV004783721" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008692...</a>
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<p>In a 25-year-old French patient with autosomal dominant polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>), <a href="#72" class="mim-tip-reference" title="Perrichot, R. A., Mercier, B., Simon, P. M., Whebe, B., Cledes, J., Ferec, C. <strong>DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients.</strong> Hum. Genet. 105: 231-239, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987650</a>] [<a href="https://doi.org/10.1007/s004390051094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987650">Perrichot et al. (1999)</a> identified what they claimed to be the fourth reported de novo mutation in the PKD1 gene: a 12628G-A transition in exon 45 leading to a trp4139-to-ter (W4139X) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10987650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0016 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, 3-BP DEL, EX20 AND 8-BP DEL, EX21
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2151766716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2151766716;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=rs2151766716" 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=rs2151766716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs748240352 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748240352;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/rs748240352?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=rs748240352" 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=rs748240352" 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=RCV000008693 OR RCV005054409" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008693, RCV005054409" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008693...</a>
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<p>In a family with autosomal dominant polycystic kidney disease (PKD1; <a href="/entry/173900">173900</a>), <a href="#9" class="mim-tip-reference" title="Bouba, I., Koptides, M., Mean, R., Costi, C.-E., Demetriou, K., Georgiou, I., Pierides, A., Siamopoulos, K., Deltas, C. C. <strong>Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families.</strong> Europ. J. Hum. Genet. 9: 677-684, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11571556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11571556</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11571556">Bouba et al. (2001)</a> identified 2 deletions in the PKD1 gene: a 3-bp deletion in exon 20 and an 8-bp deletion in exon 21. The deletions were coinherited on the same chromosome, causing disease in the mother and 3 sons. The 3-bp mutation corresponded to glycine at codon 2579. The 8-bp deletion was predicted to result in a translation frameshift after amino acid 2657, leading to a stop codon 483 bp downstream. Cloning and sequencing experiments showed that the 2 deletions were in cis position on the chromosome that was inherited from the affected mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11571556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>REFERENCES</strong>
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<a id="Aziz1993" class="mim-anchor"></a>
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Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B.
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<strong>Down-regulation of Ke6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease.</strong>
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Molec. Cell. Biol. 13: 1847-1853, 1993. Note: Erratum: Molec. Cell. Biol. 13: 6614 only, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8441417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8441417</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8441417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/mcb.13.3.1847-1853.1993" target="_blank">Full Text</a>]
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Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B.
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<strong>Coordinate regulation of 11-beta-HSD and Ke6 gene in cpk mouse: implications for steroid metabolic defect in PKD.</strong>
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Am. J. Physiol. 267: F791-F797, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7977782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7977782</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7977782" 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/10.1152/ajprenal.1994.267.5.F791" target="_blank">Full Text</a>]
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Bear, J. C., McManamon, P., Morgan, J., Payne, R. H., Lewis, H., Gault, M. H., Churchill, D. N.
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<strong>Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling.</strong>
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Am. J. Med. Genet. 18: 45-53, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6741995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6741995</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6741995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320180108" target="_blank">Full Text</a>]
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Bear, J. C., Parfrey, P. S., Morgan, J. M., Martin, C. J., Cramer, B. C.
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<strong>Autosomal dominant polycystic kidney disease: new information for genetic counselling.</strong>
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Am. J. Med. Genet. 43: 548-553, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1605247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320430309" target="_blank">Full Text</a>]
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Bhunia, A. K., Piontek, K., Boletta, A., Liu, L., Qian, F., Xu, P.-N., Germino, F. J., Germino, G. G.
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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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Cell 109: 157-168, 2002.
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[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://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'})">related citations</a>]
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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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Bogdanova, N., Markoff, A., Gerke, V., McCluskey, M., Horst, J., Dworniczak, B.
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<strong>Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.</strong>
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Genomics 74: 333-341, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11414761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11414761</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11414761" 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.2001.6568" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(00)00123-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.211191098" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.27.10.603" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.8.923" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.3.229" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.29.4.247" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.18.2617" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0596" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.18.2743" target="_blank">Full Text</a>]
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<a id="107" class="mim-anchor"></a>
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<a id="Watnick1999" class="mim-anchor"></a>
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Watnick, T., Phakdeekitcharoen, B., Johnson, A., Gandolph, M., Wang, M., Briefel, G., Klinger, K. W., Kimberling, W., Gabow, P., Germino, G. G.
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<strong>Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.</strong>
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Am. J. Hum. Genet. 65: 1561-1571, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577909[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=10577909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302657" target="_blank">Full Text</a>]
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<a id="Watson1987" class="mim-anchor"></a>
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Watson, M. L., Wright, A. F., Macnicol, A. M., Allan, P. L., Clayton, J. F., Dempster, M., Jeremiah, S. J., Corney, G., Hopkinson, D. A.
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<strong>Studies of genetic linkage between adult polycystic kidney disease and three markers on chromosome 16.</strong>
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J. Med. Genet. 24: 457-461, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2821260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2821260</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2821260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.24.8.457" 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="Wunderle1994" class="mim-anchor"></a>
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Wunderle, V., Ramkissoon, Y. D., Kwok, C., Korn, R. M., King, V. E., Goodfellow, P. N.
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<strong>Breakpoint break for consortium studying adult polycystic kidney disease.</strong>
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Cell 77: 785-786, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8004666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8004666</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8004666" 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/10.1016/0092-8674(94)90123-6" target="_blank">Full Text</a>]
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<a id="Xu2001" class="mim-anchor"></a>
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Xu, G. M., Sikaneta, T., Sullivan, B. M., Zhang, Q., Andreucci, M., Stehle, T., Drummond, I., Arnaout, M. A.
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<strong>Polycystin-1 interacts with intermediate filaments.</strong>
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J. Biol. Chem. 276: 46544-46552, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11581269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11581269</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11581269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M107828200" target="_blank">Full Text</a>]
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Young, A. E., Biller, D. S., Herrgesell, E. J., Roberts, H. R., Lyons, L. A.
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<strong>Feline polycystic kidney disease is linked to the PKD1 region.</strong>
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Mammalian Genome 16: 59-65, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674734</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15674734" 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/s00335-004-2412-2" target="_blank">Full Text</a>]
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Zerres, K., Rudnik-Schoneborn, S., Deget, F., Beetz, R., Brodehl, J., Kuwertz-Broking, E., Muller-Wiefel, D., Rascher, W., Ruder, H., Scharer, K., Weber, H. P.
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<strong>Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk.</strong>
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J. Med. Genet. 30: 583-588, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8411032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8411032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8411032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.30.7.583" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/20/2018
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Patricia A. Hartz - updated : 1/15/2014<br>George E. Tiller - updated : 11/14/2011<br>Patricia A. Hartz - updated : 8/10/2011<br>George E. Tiller - updated : 4/1/2010<br>George E. Tiller - updated : 4/1/2010<br>George E. Tiller - updated : 3/30/2010<br>George E. Tiller - updated : 3/3/2010<br>Patricia A. Hartz - updated : 12/10/2009<br>Patricia A. Hartz - updated : 1/25/2008<br>Victor A. McKusick - updated : 6/8/2007<br>George E. Tiller - updated : 5/21/2007<br>Patricia A. Hartz - updated : 6/2/2006<br>Patricia A. Hartz - updated : 4/7/2006<br>Patricia A. Hartz - updated : 2/8/2006<br>Patricia A. Hartz - updated : 6/2/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Marla J. F. O'Neill - updated : 1/19/2005<br>Patricia A. Hartz - updated : 1/18/2005<br>Victor A. McKusick - updated : 2/2/2004<br>Victor A. McKusick - updated : 12/23/2003<br>George E. Tiller - updated : 6/19/2003<br>Victor A. McKusick - updated : 2/3/2003<br>Victor A. McKusick - updated : 1/13/2003<br>George E. Tiller - updated : 12/4/2002<br>Victor A. McKusick - updated : 11/25/2002<br>Patricia A. Hartz - updated : 10/29/2002<br>George E. Tiller - updated : 9/18/2002<br>Patricia A. Hartz - updated : 7/1/2002<br>Victor A. McKusick - updated : 6/14/2002<br>George E. Tiller - updated : 5/2/2002<br>Stylianos E. Antonarakis - updated : 5/1/2002<br>Victor A. McKusick - updated : 4/4/2002<br>Michael B. Petersen - updated : 2/28/2002<br>Victor A. McKusick - updated : 10/29/2001<br>Stylianos E. Antonarakis - updated : 8/7/2001<br>George E. Tiller - updated : 1/29/2001<br>Victor A. McKusick - updated : 1/24/2001<br>Stylianos E. Antonarakis - updated : 12/14/2000<br>George E. Tiller - updated : 10/17/2000<br>Victor A. McKusick - updated : 9/14/2000<br>Victor A. McKusick - updated : 2/2/2000<br>Victor A. McKusick - updated : 12/17/1999<br>Victor A. McKusick - updated : 12/7/1999<br>Victor A. McKusick - updated : 6/28/1999<br>Stylianos E. Antonarakis - updated : 12/23/1998<br>Victor A. McKusick - updated : 8/3/1998<br>Victor A. McKusick - updated : 11/26/1997<br>Victor A. McKusick - updated : 9/30/1997<br>Victor A. McKusick - updated : 9/22/1997<br>Victor A. McKusick - updated : 8/12/1997<br>Victor A. McKusick - updated : 7/14/1997<br>Ada Hamosh - updated : 7/10/1997<br>Victor A. McKusick - updated : 6/26/1997<br>Victor A. McKusick - updated : 6/17/1997<br>Victor A. McKusick - updated : 6/2/1997<br>Moyra Smith - updated : 9/11/1996<br>Moyra Smith - updated : 8/27/1996
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Moyra Smith : 6/19/1996
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carol : 06/27/2024
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alopez : 06/22/2022<br>carol : 01/22/2020<br>alopez : 05/16/2019<br>alopez : 11/20/2018<br>carol : 08/08/2017<br>carol : 08/07/2017<br>carol : 07/25/2016<br>carol : 08/18/2015<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>carol : 9/30/2013<br>carol : 4/12/2013<br>terry : 11/27/2012<br>terry : 11/13/2012<br>carol : 11/15/2011<br>terry : 11/14/2011<br>mgross : 8/11/2011<br>mgross : 8/11/2011<br>mgross : 8/11/2011<br>terry : 8/10/2011<br>alopez : 4/21/2011<br>wwang : 1/13/2011<br>carol : 10/4/2010<br>carol : 5/20/2010<br>wwang : 4/7/2010<br>terry : 4/1/2010<br>terry : 4/1/2010<br>terry : 4/1/2010<br>wwang : 3/31/2010<br>terry : 3/30/2010<br>wwang : 3/12/2010<br>terry : 3/3/2010<br>mgross : 12/10/2009<br>terry : 12/10/2009<br>mgross : 10/16/2009<br>carol : 2/26/2009<br>mgross : 1/28/2008<br>terry : 1/25/2008<br>wwang : 8/22/2007<br>alopez : 6/12/2007<br>terry : 6/8/2007<br>wwang : 6/4/2007<br>terry : 5/21/2007<br>mgross : 6/8/2006<br>mgross : 6/8/2006<br>terry : 6/2/2006<br>mgross : 4/14/2006<br>terry : 4/7/2006<br>wwang : 3/2/2006<br>wwang : 2/15/2006<br>terry : 2/8/2006<br>wwang : 6/8/2005<br>wwang : 6/6/2005<br>terry : 6/2/2005<br>wwang : 5/27/2005<br>wwang : 3/21/2005<br>wwang : 3/18/2005<br>terry : 3/15/2005<br>carol : 1/20/2005<br>terry : 1/19/2005<br>mgross : 1/18/2005<br>tkritzer : 1/14/2005<br>terry : 2/2/2004<br>cwells : 12/29/2003<br>terry : 12/23/2003<br>cwells : 7/8/2003<br>cwells : 6/19/2003<br>alopez : 2/25/2003<br>carol : 2/13/2003<br>carol : 2/13/2003<br>tkritzer : 2/4/2003<br>terry : 2/3/2003<br>alopez : 1/13/2003<br>alopez : 1/13/2003<br>alopez : 1/13/2003<br>alopez : 1/13/2003<br>tkritzer : 1/13/2003<br>cwells : 12/4/2002<br>cwells : 11/25/2002<br>terry : 11/20/2002<br>mgross : 10/29/2002<br>cwells : 9/18/2002<br>carol : 7/1/2002<br>carol : 7/1/2002<br>cwells : 6/18/2002<br>terry : 6/14/2002<br>cwells : 5/14/2002<br>cwells : 5/2/2002<br>mgross : 5/1/2002<br>mgross : 5/1/2002<br>cwells : 4/15/2002<br>cwells : 4/10/2002<br>terry : 4/4/2002<br>cwells : 3/6/2002<br>cwells : 3/6/2002<br>cwells : 2/28/2002<br>carol : 11/1/2001<br>mcapotos : 10/31/2001<br>terry : 10/29/2001<br>mgross : 8/7/2001<br>mcapotos : 2/1/2001<br>mcapotos : 1/29/2001<br>mcapotos : 1/26/2001<br>cwells : 1/26/2001<br>terry : 1/24/2001<br>carol : 12/23/2000<br>mgross : 12/14/2000<br>alopez : 10/17/2000<br>mcapotos : 10/5/2000<br>mcapotos : 9/26/2000<br>terry : 9/14/2000<br>mcapotos : 8/3/2000<br>mcapotos : 3/30/2000<br>mcapotos : 3/27/2000<br>mcapotos : 3/21/2000<br>mgross : 3/8/2000<br>terry : 2/9/2000<br>carol : 2/4/2000<br>terry : 2/2/2000<br>terry : 2/2/2000<br>mgross : 12/28/1999<br>terry : 12/17/1999<br>mcapotos : 12/9/1999<br>terry : 12/7/1999<br>carol : 12/1/1999<br>carol : 7/9/1999<br>jlewis : 7/7/1999<br>terry : 6/28/1999<br>carol : 12/23/1998<br>psherman : 10/9/1998<br>terry : 8/11/1998<br>terry : 8/3/1998<br>terry : 6/26/1998<br>terry : 6/4/1998<br>alopez : 5/21/1998<br>carol : 5/19/1998<br>jenny : 12/2/1997<br>terry : 11/26/1997<br>terry : 11/10/1997<br>jenny : 9/30/1997<br>terry : 9/26/1997<br>mark : 9/23/1997<br>terry : 9/22/1997<br>mark : 8/15/1997<br>terry : 8/12/1997<br>mark : 7/16/1997<br>mark : 7/16/1997<br>terry : 7/14/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>jenny : 7/1/1997<br>terry : 6/26/1997<br>terry : 6/23/1997<br>terry : 6/23/1997<br>terry : 6/17/1997<br>mark : 6/2/1997<br>terry : 6/2/1997<br>jamie : 1/21/1997<br>mark : 1/8/1997<br>jamie : 12/18/1996<br>mark : 12/13/1996<br>mark : 10/17/1996<br>terry : 10/10/1996<br>mark : 9/11/1996<br>mark : 9/11/1996<br>mark : 9/10/1996<br>mark : 9/10/1996<br>mark : 9/10/1996<br>mark : 9/10/1996<br>mark : 9/10/1996<br>mark : 9/10/1996<br>mark : 8/27/1996<br>mark : 6/20/1996<br>mark : 6/19/1996<br>mark : 6/19/1996
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POLYCYSTIN 1; PKD1
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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PKD1 GENE<br />
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PBP
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PKD1</em></strong>
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Cytogenetic location: 16p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:2,088,708-2,135,898 </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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16p13.3
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Polycystic kidney disease 1
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<span class="mim-font">
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173900
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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>Polycystin-1, encoded by the PKD1 gene, forms a complex with polycystin-2 (PKD2; 173910) that regulates multiple signaling pathways to maintain normal renal tubular structure and function (summary by Song et al., 2009). </p>
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<strong>Cloning and Expression</strong>
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<p>Characterization of the PKD1 gene had been complicated by rearrangements on chromosome 16 resulting in homologous regions in 16p termed the homologous gene (HG) area. All but 3.5 kb at the 3-prime end of the PKD1 transcript (which is approximately 14 kb in total) is encoded by a region reiterated several times in the HG area. The HG region encodes 3 large transcripts of 21 kb (HG-A), 17 kb (HG-B), and 8.5 kb (HG-C), and although these have 3-prime ends that differ from PKD1, they share substantial homology to the PKD1 transcript over most of their length. It was not known, however, whether the HG transcripts produce functional proteins (summary by Hughes et al., 1995). </p><p>To overcome cloning problems caused by the HG region, Hughes et al. (1995) isolated the full PKD1 gene using an exon-linking strategy. They took RNA from a cell line containing PKD1 but not the duplicate HG loci and cloned a cDNA contig of the entire PKD1 transcript. The predicted PKD1 protein, called polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The N-terminal extracellular region of over 2,500 amino acids contains leucine-rich repeats, a C-type lectin, 16 immunoglobulin-like repeats, and 4 type III fibronectin-related domains. The findings indicated that polycystin is an integral membrane protein involved in cell-cell/matrix interactions. </p><p>The International Polycystic Kidney Disease Consortium (1995) reported the complete structure of the PKD1 gene and its protein. The PKD1 transcript contains 46 exons. The 14.5-kb PKD1 transcript encodes a 4,304-amino acid protein that has a novel domain architecture. The N-terminal half of the protein consists of a mosaic of previously described domains, including leucine-rich repeats flanked by characteristic cysteine-rich structures, LDL-A and C-type lectin domains, and 14 units of a novel 80 amino acid domain. The presence of these domains suggested that the PKD1 protein is involved in adhesive protein-protein and protein-carbohydrate interactions in the extracellular compartment. They proposed a hypothesis that links the predicted properties of the protein with the phenotypic features of autosomal dominant PKD. </p><p>In a study of PKD1 mRNA with an RNase protection assay, Ward et al. (1996) found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein was assessed in kidney, using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining was restricted to epithelial cells. Expression in the developing nephron was most prominent in mature tubules, with lesser staining in Bowman capsule and the proximal ureteric bud. In later fetal and adult kidney, strong staining persisted in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. The authors suggested that the major role of polycystin is in the maintenance of renal epithelial differentiation and organization from early fetal life. Polycystin expression, monitored at the mRNA level and by immunohistochemistry, appeared higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein. </p><p>Ibraghimov-Beskrovnaya et al. (1997) assembled an authentic full-length PKD1 cDNA and demonstrated expression of polycystin in vitro. Polyclonal antibodies directed against distinct extra- and intracellular domains specifically immunoprecipitated in vitro translated polycystin. The panel of antibodies was used to determine localization of polycystin in renal epithelial and endothelial cell lines and tissues of fetal, adult, and cystic origins. In normal adult kidney and maturing fetal nephrons, polycystin expression was confined to epithelial cells of the distal nephron and vascular endothelial cells. Expression in the proximal nephron was observed only after injury-induced cell proliferation. Polycystin expression was confined to ductal epithelium in liver, pancreas, and breast, and restricted to astrocytes in normal brain. The investigators found clear evidence for the membrane localization of polycystin by both tissue sections and by confocal microscopy in cultured renal and endothelial cells. When cultured cells made cell-cell contact, polycystin was localized to the lateral membranes of cells in contact. The data suggested that polycystin probably has a widespread role in epithelial cell differentiation and maturation and in cell-cell interactions. </p>
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<strong>Gene Function</strong>
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<p>It had been 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 the PKD2 gene product, polycystin-2 (173910). 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 up-regulation 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>Grimm et al. (2003) found that mammalian polycystin-1 localized to the cell surface and endoplasmic reticulum (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>A large proportion of the extracellular N terminus of polycystin-1 is composed of 15 tandemly repeated PKD repeats (Ibraghimov-Beskrovnaya et al., 2000). Situated between the last PKD repeat and the first transmembrane segment is the receptor for 'egg jelly' (REJ) domain, which was originally described in sea urchin. Immediately following this domain is a G protein-coupled receptor proteolytic site (GPS) domain (Delmas et al., 2002). Qian et al. (2002) demonstrated that polycystin-1 undergoes cleavage at the GPS domain in a process that requires the REJ domain. Most of the N-terminal fragment remains tethered at the cell surface, although a small amount is secreted. PKD1-associated mutations in the REJ domain disrupt cleavage, abolish the ability of polycystin-1 to activate signal transducer and activator of transcription-1, and induce tubulogenesis in vitro. Qian et al. (2002) concluded that cleavage of polycystin-1 is likely essential for its biologic activity. </p><p>Using antibodies raised against various domains of polycystin-1 and against specific adhesion complex proteins, Scheffers et al. (2000) determined that polycystin-1 was detected in the cytoplasm as well as colocalizing with desmosomes of Madin-Darby canine kidney (MDCK) cells, but not with tight or adherens junctions. They further confirmed the desmosomal localization using confocal laser scanning and immunoelectron microscopy. By performing a calcium switch experiment, the authors demonstrated the sequential reassembly of tight junctions, subsequently adherens junctions, and finally desmosomes. Polycystin-1 stained the membrane only after incorporation of desmoplakin (125647) into the desmosomes, suggesting that membrane-bound polycystin-1 may be important for cellular signaling or cell adhesion, but not for the assembly of adhesion complexes. </p><p>Because signaling from cell-cell and cell-matrix adhesion complexes regulates cell proliferation and polarity, Huan and van Adelsberg (1999) speculated that polycystin-1 may interact with these complexes. They showed that polycystin-1 colocalizes with the cell adhesion molecules E-cadherin (CDH1; 192090) and alpha- (116805), beta- (116806), and gamma-catenin. Polycystin-1 coprecipitated with these proteins and comigrated with them on sucrose density gradients, but it did not colocalize, coprecipitate, or comigrate with focal adhesion kinase (600758), a component of the focal adhesion. Huan and van Adelsberg (1999) concluded that polycystin-1 is in a complex containing E-cadherin and alpha-, beta-, and gamma-catenin. These observations raised the question of whether the defects in cell proliferation and cell polarity observed in PKD are mediated by E-cadherin or the catenins. </p><p>Rodova et al. (2002) presented evidence for beta-catenin-induced expression of PKD1. They analyzed the promoter region of PKD1 and identified numerous transactivating factors, including 4 T-cell factor (TCF)-binding elements (TBEs). Beta-catenin induced a reporter construct containing TBE1 6-fold when cotransfected into HEK293T cells, which express TCF4 (TCF7L2; 602228). Dominant-negative TCF4 or deletion of the TBE1 sequence inhibited the induction. Gel shift assays confirmed that TCF4 and beta-catenin could complex with the TBE1 site, and HeLa cells stably transfected with beta-catenin responded with elevated levels of endogenous PKD1 mRNA. Rodova et al. (2002) concluded that the PKD1 gene is a target of the beta-catenin/TCF pathway. </p><p>Ibraghimov-Beskrovnaya et al. (2000) showed that polycystin-1 is localized to cell-cell contacts in kidney epithelial cell (MDCK) cultures. In vitro binding assays demonstrated that the Ig-like domains XI to XVI form interactions with high affinity, while domains II to V interact with a lower affinity. Antibodies raised against Ig-like domains of polycystin-1 disrupted cell-cell interactions in MDCK cell monolayers. The authors hypothesized that interactions of the Ig-like repeats of polycystin-1 play an important role in mediating intercellular adhesion, and that loss of these interactions due to mutations in polycystin-1 may be an important step in cystogenesis. </p><p>Boletta et al. (2000) described a novel cell culture system for studying how PKD1 regulates the later stages of renal tubular differentiation. They showed that expression of human PKD1 in MDCK cells slowed their growth and protected them from programmed cell death. MDCK cells expressing PKD1 also spontaneously formed branching tubules, while control cells formed simple cysts. Increased cell proliferation and apoptosis have been implicated in the pathogenesis of cystic diseases. This study suggested that PKD1 may function to regulate both pathways, allowing cells to enter a differentiation pathway that results in tubule formation. </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>Xu et al. (2001) provided experimental evidence for the interaction of polycystin-1 with the intermediate filament network. They found that vimentin (193060) binds the C terminus of mouse polycystin-1 in a yeast 2-hybrid screen of canine kidney cells. Deletion of the coiled-coil sequence from either peptide abolished the interaction. By GST pull-down and in vitro filament assembly analyses, they also found the cytokeratins K8 (KRT8; 148060) and K18 (KRT18; 148070) able to bind the coiled-coil region of polycystin-1. Immunolocalization of endogenous polycystin-1 in canine kidney cells revealed discrete nodular junctional staining that overlapped staining for cytokeratin and desmoplakin (125647). With use of 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-1 purified from transgenic mouse kidney cells was heavily N-glycosylated, and both endoglycosidase (Endo-H)-sensitive and mature Endo-H-resistant forms of the protein were 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 complex glycosylation and insertion into the plasma membrane. </p><p>Bukanov et al. (2002) utilized a 3-dimensional MDCK in vitro model of tubulogenesis and cystogenesis to demonstrate that polycystin-1 is a novel component of desmosomal junctions of epithelial cells. Downregulation of polycystin-1 mRNA was detected in cysts as compared to tubules, leading to altered protein expression and localization. While polycystin-1 was localized to basolateral membranes of MDCK tubules, it was only detected in cytoplasmic pools in cystic cells. Polycystin-1 was not detected in intercellular contacts at early steps of tubulogenesis, but assumed its basolateral localization at the time of cell polarization and lumen formation. During a similar morphologic process, upregulation of polycystin-1 mRNA and protein levels was noted as a pancreatic ductal epithelial cell line underwent in vitro differentiation, resulting in dome formation. The authors suggested that the loss of polycystin-1 from its basolateral location in tubular epithelium may alter critical pathways controlling normal tubulogenesis leading to cystic transformation. </p><p>ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of NO. Thus, eNOS (163729) could have a modifier effect in ADPKD. To test this hypothesis, Persu et al. (2002) genotyped 173 unrelated European ADPKD patients for the glu298-to-asp (163729.0001), intron 4 VNTR, and -786T-C (163729.0002) polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In 93 males, the glu298-to-asp polymorphism was associated with a lower age at ESRD. This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NOS activity was decreased in renal artery samples from PKD males harboring the asp298 allele, in association with posttranslational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. Persu et al. (2002) concluded that glu298-to-asp is associated with a 5 year lower mean age at ESRD in a subset of ADPKD males. They hypothesized that the effect could be due to decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO. </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>In mouse kidneys and MDCK cell lines, Chauvet et al. (2004) demonstrated that polycystin-1 undergoes proteolytic cleavage that releases its C-terminal tail, which enters the nucleus and initiates signaling processes. Using a ureteral ligation mouse model, they showed that the cleavage occurs in vivo in association with alterations in mechanical stimuli. Polycystin-2 was observed to modulate the signaling properties of the polycystin-1 C-terminal tail. Chauvet et al. (2004) concluded that this represents a pathway by which polycystin-1 transmits messages directly to the nucleus. </p><p>Following its nuclear translocation in MDCK cells, Low et al. (2006) found that the C-terminal tail of human polycystin-1 interacted with Stat6 (601512) and P100 (602181) and stimulated Stat6-dependent gene expression. Under normal conditions, Stat6 localized to primary cilia of renal epithelial cells; however, cessation of apical fluid flow resulted in its nuclear translocation. Cyst-lining cells in ADPKD exhibited elevated levels of nuclear STAT6, P100, and the polycystin-1 C-terminal tail. Exogenous expression of the human polycystin-1 C-terminal tail resulted in renal cyst formation in zebrafish embryos. Low et al. (2006) concluded that upregulation of the STAT6/P100 pathway by the polycystin-1 C-terminal tail leads to the cellular changes characteristic of renal cysts. </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>Shillingford et al. (2006) found that the cytoplasmic tail of PC1 interacted with tuberin (191092), a regulator of MTOR (FRAP1; 601231) kinase activity, and that the MTOR pathway was inappropriately activated in cyst-lining epithelial cells from human ADPKD patients and mouse models. Rapamycin, an inhibitor of MTOR, was effective in reducing renal cystogenesis in 2 independent mouse models of PKD, and it appeared to reduce renal cysts, at least partially, by selective induction of apoptosis and luminal shedding of cyst-lining epithelial cells. Advanced-stage ADPKD patients frequently receive a renal transplant without removal of the affected cystic kidneys, and rapamycin is often used to prevent transplant rejection. Shillingford et al. (2006) found that patients treated with rapamycin had a statistically significant reduction in native polycystic kidney size over a period of 24 months compared with patients treated with other antirejection drugs. </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>
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Su et al. (2018) reported the 3.6-angstrom cryoelectron microscopy structure of truncated human PKD1-PKD2 (173910) 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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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>Reeders et al. (1985) showed that the PKD1 locus is closely linked to the alpha-globin locus (HBA1; 141800) on 16p (lod = 25.85, theta = 0.05, 99% confidence limits = 2-11 cM). In establishing this linkage, they used a highly polymorphic region about 8 kb beyond the 3-prime end of the alpha-globin cluster (3-prime-HVR = 3-prime-hypervariable region). In the Oxford data (Reeders, 1985), ADPKD versus phosphoglycolate phosphatase (PGP; 172280) showed a lod score of 8.21 at theta = 0.0. PGP and HBA showed a lod score of 11.61 at theta = 0.0. In 13 South Wales kindreds, Lazarou et al. (1987) found a maximum lod score of 24.187 at a recombination fraction of 0.03 for linkage between PKD1 and alpha-globin. Despite phenotypic heterogeneity, they found no evidence of linkage heterogeneity. </p><p>Watson et al. (1987) found tight linkage of ADPKD and PGP; the maximum likelihood value of the recombination fraction was 0.0 with a lod score of 5.5. Together with the ADPKD versus HVR linkage data, these findings suggested to them that ADPKD and PGP are on the 5-prime side of the alpha-globin cluster. The polarity of the HBAC gene cluster viz-a-viz the centromere is unknown. The recombination fraction for the 3-prime-HVR and ADPKD is somewhat greater in males than in females (Reeders, 1986)--an anomalous finding. Reeders et al. (1985) found no definite recombination between PGP and ADPKD. HBAC is distal to ADPKD but whether PGP is proximal or distal to ADPKD is unknown. The evidence on location of HBAC was conflicting, with assignments from 16p13.11 to 16p13.33. Reeders et al. (1988) described an array of linked markers that bracket the PKD1 locus. Germino et al. (1990) demonstrated a DNA marker, D16S84, that showed no recombination with PKD1 in 201 informative meioses. </p><p>Pound et al. (1992) presented evidence for linkage disequilibrium between PKD1 and D16S94. Breuning et al. (1990) further defined the location of markers on 16p in the vicinity of the PKD1 locus. Harris et al. (1991) identified closely linked microsatellite polymorphisms that could be used in a PCR-based assay for a rapid, inexpensive, and nonradioactive method of linkage analysis. </p><p>Gal et al. (1989) studied 10 families in which early manifestation of the disorder was a frequent finding. In all families studied, close linkage was observed between the chromosome 16 alpha-globin marker and the ADPKD locus. They concluded that there is no evidence for genetic heterogeneity of ADPKD in families with early- and later-onset disease. In 28 northern European pedigrees from England, Scotland, Holland, and eastern Finland, Reeders et al. (1987) found no evidence of heterogeneity of the linkage of PKD1 with alpha-globin. (The recessive form of early-onset polycystic kidney disease is probably not linked to HBA (Reeders, 1986).) </p><p>Zerres et al. (1993) also investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease (ADPKD). They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined as clinical manifestations (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. A strong familial clustering for early manifesting ADPKD was found; out of the total of 65 sibs of the 64 index patients, 15 showed comparably early manifestation. Another 10 symptom-free children were diagnosed sonographically as having ADPKD before the age of 18 years. The authors noted that high recurrence risk to sibs has important implications for genetic counseling and clinical care of affected families. </p><p>Among the same 17 families reported by Bear et al. (1984, 1992), Parfrey et al. (1990) found that polycystic kidney disease cosegregated with polymorphic DNA markers flanking the PKD1 locus in 10; in 2 families cosegregation did not occur, and in 5 families linkage could not be determined because of uninformativeness of the markers. </p><p>Ryynanen et al. (1987) did linkage studies in a 4-generation Finnish family with polycystic kidney disease; all affected members of the extended pedigree were asymptomatic and none had developed renal failure. They showed that the mutation in this family was closely linked to the alpha-globin cluster. This might be an allelic disorder. Using DNA from a set of multigenerational families from CEPH (Centre d'etude polymorphisme humaine, Paris), Keith et al. (1987) constructed a genetic map of chromosome 16 based on 40 polymorphic DNA markers. The map spanned 142 cM in males, somewhat larger than the 108 cM previously estimated by chiasma counts. Males had higher recombination fractions near the alpha-globin gene cluster, but females showed higher recombination in other regions. </p><p>Germino et al. (1992) demonstrated that the PKD1 gene lies within an extremely CpG-rich 750-kb segment of 16p13.3. Its genetic localization with respect to physically mapped markers in this segment was refined by Somlo et al. (1992). </p><p>In the Spanish population, Peral et al. (1993) typed 31 families from different geographic areas using marker loci flanking PKD1 on 16p. Multilocus linkage analysis indicated that in 26 families the disease resulted from PKD1 mutations, whereas in 3 families it resulted from mutations in a locus other than PKD1; 2 other families were not informative. Using the HOMOG test, they estimated that PKD1-linked mutations were responsible for 85% of families with PKD in Spain. </p><p>The 400-Mb genome of the Japanese pufferfish, Fugu rubripes, is relatively free of repetitive DNA and contains genes with small introns at high density. Sandford et al. (1996) demonstrated that the genes that are mutant in polycystic kidney disease-1 and tuberous sclerosis-2 (TSC2; 191092) are conserved in the Fugu genome where they are tightly linked. In addition, sequences homologous to the SSTR5 gene (182455) were identified 5-prime to PKD1, defining a larger syntenic region. As in genomes of mouse and human, the Fugu TSC2 and PKD1 genes are adjacent in a tail-to-tail orientation. </p><p><strong><em>PKD1 Pseudogenes</em></strong></p><p>
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A large part of the PKD1 gene is duplicated in an unknown number of homologous genes (HG) which are located on chromosome 16p13.1 and share approximately 95% homology with the PKD1 gene (Hughes et al., 1995). Bogdanova et al. (2001) examined the expression of 5 of these homologous genes located proximal to PKD1. They used RT-PCR of total RNA and mRNA associated within polysomes isolated from a human glioblastoma cell line in which polycystins are well expressed. Analysis of the products suggested that the homologs produce mRNA species with suboptimal start codons and that these mRNA species are not translated. Bogdanova et al. (2001) concluded that the homologs are pseudogenes. </p>
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<p>To elucidate the molecular pathways that modulate renal cyst growth in ADPKD, Song et al. (2009) used cDNA microarray gene profiling of cysts of different size and minimally cystic tissue (MCT) from 5 PKD1 human polycystic kidneys. The authors found downregulation of kidney epithelial-restricted genes (e.g., nephron segment-specific markers and cilia-associated cystic genes such as HNF1B (189907), PKHD1 (606702), IFT88 (600595), and CYS1) in the PKD1 renal cysts. Upregulated genes in PKD1 cysts included those associated with renal development, mitogen-mediated proliferation, cell cycle progression, epithelial-mesenchymal transition, hypoxia, aging, and immune/inflammatory responses. The authors suggested that upregulated signaling of Wnt/beta-catenin, pleiotropic growth factors, such as VEGF (192240), and G protein-coupled receptors, such as PTGER2 (176804), was associated with renal cystic growth. By integrating these pathways with a number of dysregulated networks of transcription factors, including SRF (600589), Song et al. (2009) suggested that epithelial dedifferentiation accompanied by aberrant activation and crosstalk of specific signaling pathways may be required for PKD1 cyst growth and disease progression. </p>
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<p>Hughes et al. (1995) determined that the 14,148-bp PKD1 transcript is distributed among 46 exons spanning 52 kb. </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). The PKD1 promoter also contains an E box, MINI (muscle initiator sequence) motif, and a binding site for AP2 (107580). Deletion studies of the mouse Pkd1 promoter identified a 280-bp fragment capable of driving reporter gene expression, whereas reporter constructs containing larger fragments of the promoter showed lower activity. Mutating a potential E2f-binding site within the 280-bp fragment diminished reporter activity, suggesting a role for E2F in regulating cell cycle-dependent expression of the PKD1 gene. </p>
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<p>The European Polycystic Kidney Disease Consortium (1994) isolated a gene encoding a 14-kb transcript that was disrupted by a chromosome translocation in a family with PKD1 (173900). Indeed, the unusual Portuguese family had both PKD and tuberous sclerosis (TSC2; 191092), which maps to the same region of 16p. The mother had a balanced translocation, 46,XX t(16;22)(p13.3;q11.21), which was inherited by her daughter. The son, on the other hand, had an unbalanced karyotype 45,XY with monosomy for 16pter-p13.3 as well as for 22pter-q11.21. This individual had the clinical phenotype of tuberous sclerosis which was thought to be due to the fact that the TSC2 locus located within 16p13.3 was deleted in the unbalanced karyotype. The mother and the daughter with the balanced translocation had the clinical features of PKD1, while the parents of the mother were cytogenetically normal, with no clinical features of tuberous sclerosis and no renal cysts on ultrasound examination. The location of the breakpoint in the balanced translocation was more than 20 kb proximal to the TSC2 locus. The consortium isolated a gene spanning the breakpoint and designated it PBP (for 'polycystic breakpoint'). They then identified mutations in the PBP gene in other patients with PKD1. The first mutation found was a 5.5-kb genomic deletion within the 3-prime end of the PBP gene in an affected woman and in paraffin-embedded tissue from her affected father (deceased at the time of report). The second rearrangement detected was a 2-kb genomic deletion within the PBP gene which was found to have a frameshift deletion of 446 bp (between basepairs 1746 and 2192). This was a de novo mutation. Sequencing of genomic DNA in another patient demonstrated a G-to-C transition at the +1 position of the splice donor site following the 135-bp exon (601313.0001). The splicing defect resulted in an in-frame deletion of 135-bp from the PBP transcript (basepairs 3696 to 3831). A fourth patient was described in which both the TSC2 gene and the PKD1 gene were deleted. Further study indicated that the deletion extended over approximately 100 kb and deleted most, if not all, of the PKD1 gene. By 'zoo blotting,' the consortium demonstrated that the PKD1 gene is conserved in other mammalian species, including horse, dog, pig, and rodents. No related sequences were seen by hybridization at normal stringency in chicken, frog, or fruit fly. Wunderle et al. (1994) pointed out that 3 explanations are classically used to account for dominant inheritance in a disorder such as PKD1: haploinsufficiency, gain-of-function mutations (including dominant negative effects), and 2-hit mechanisms (a second somatic mutation being required to give rise to defective cells). </p><p>Harris et al. (1990) found that the region around the PKD1 locus is unusually rich in CpG dinucleotides. In a search for the gene that is mutant in polycystic kidney disease, Gillespie et al. (1991) concentrated on CpG islands in a region between 2 markers that flank the PKD1 locus and are separated by less than 750 kb. One of the genes so marked, ATP6C (108745), was isolated from HeLa and cultured cystic kidney epithelial cell cDNA libraries. It was found to encode a 155-amino acid peptide having 4 putative transmembrane domains. The corresponding transcript was found in all tissues tested but was most abundant in brain and kidney. The deduced amino acid sequence showed 93% similarity to part of the proton channel of vacuolar H(+)-ATPase. Because of the possible role of a mutated proton channel in the pathogenesis of cystic disease, Gillespie et al. (1991) sequenced cDNAs corresponding to both alleles of an affected individual but found no differences in the deduced amino acid sequence. Moreover, transcript size and abundance were not altered in cystic kidney. </p><p>Peral et al. (1995) sought mutations in the PKD1 gene in this disorder. Analysis of 3 regions in the 3-prime part of the gene revealed 2 mutations that occurred by a novel mechanism. Both were deletions (of 18 or 20 bp) within the same 75-bp intron and, although these deletions did not disrupt the splice donor or acceptor sites at the boundary of the intron, they nevertheless resulted in aberrant splicing. Two different transcripts were produced in each case; one included the normally deleted intron while the other had a 66-bp deletion due to activation of a cryptic 5-prime splice site. No normal product was generated from the deletion-mutant gene. Peral et al. (1995) speculated that aberrant splicing probably occurred because the deletion made the intron too small for spliceosome assembly using the authentic splice sites. They also identified a 9-bp direct repeat within the intron, which probably facilitated the intronic deletion by promoting misalignment of sequence. </p><p>At a point when only 7 mutations in the PKD1 gene had been described, Peral et al. (1996) reported a systematic screen covering nearly 80% of the approximately 2.5 kb of translated transcript that is encoded by a single-copy DNA. They identified and characterized 6 novel mutations that, together with the previously described changes, amounted to a detection rate of 10 to 15% in the population studied. Study of the PKD1 mutation search in the PKD1 gene is complicated by the fact that most of the gene lies in a genomic region reiterated several times elsewhere on chromosome 16. The results of the study of Peral et al. (1996) have important implications for genetic diagnosis of PKD1 because they indicate that most of the mutations lie within the duplicated area which is difficult to study. They provided a diagram of the structure of the polycystin protein with an indication of the site of the mutations described to date. Comparison of the phenotypes of patients with large frameshifting or terminating changes and those with more subtle in-frame changes showed no obvious differences, suggesting that they may all be inactivating changes. They cited evidence of an alternatively spliced form of PKD1 that contains an additional exon in intron 16. Inclusion of this exon would change the reading frame and result in the production of a much smaller protein product. Hence they suggested that all PKD1 mutations may be inactivating, but those in typical families disrupt just the full-length polycystin, whereas those associated with large deletions disrupt both forms of the PKD1 protein, resulting in a more severe, early-onset disease. </p><p>Neophytou et al. (1996) identified an intragenic polymorphism in the coding region of the gene. Alanine at position 4091 is encoded by either GCA or GCG. In the Cypriot population this polymorphism had a heterozygosity of 35%. Neophytou et al. (1996) reported that this polymorphism is readily detectable with the enzyme Bsp1286I. They considered this intragenic polymorphism to be highly useful in informative families, given the instability of the PKD1 region. They also identified a 12258T-A mutation that led to premature termination of translation (601313.0006). </p><p>Reeders (1992) put forward an interesting 2-hit mutational hypothesis for PKD1. He pointed out the several unusual features such as the absence of detectable abnormalities in most nephrons; even in the end-stage disease, less than 10% of the roughly 1 million nephrons in each kidney contain cysts. Furthermore, any segment of the nephron, from the glomerulus to the collecting duct, may harbor a cyst. The hypothesis suggests that at the sites of cyst formation, a somatic mutation occurs in the chromosome 16 that does not carry the inherited mutation. A prediction of the 2-hit model is that renal cysts will occasionally be found in persons without an inherited predisposition as a result of 2 somatic mutations occurring in a single cell. One or 2 renal cysts are a common radiologic finding in the general population and the probability of finding a cyst in an individual does, as predicted, rise with age. The 2-hit model predicts that the number of cysts would increase with age in PKD1. </p><p>ADPKD is characterized by progressive cyst formation in a variety of organs outside the kidney, including liver and pancreas. Using DNA from the liver cysts of 2 donors with ADPKD, Watnick et al. (1998) showed that intragenic, somatic mutations (frameshifts, nonsense codons, severe splicing mutations, and loss of heterozygosity) are common in hepatic cysts. All pathogenic mutations were shown to have altered the previously normal copy of the gene. These data extend the 2-hit model of cystogenesis to include a second focal manifestation of the disease. </p><p>Qian et al. (1996) developed a novel method for isolating renal cystic epithelia from single cysts and showed that individual renal cysts in PKD1 are monoclonal. Loss of heterozygosity (LOH) was discovered within a subset of cysts for 2 closely linked polymorphic markers located within the PKD1 gene. Genetic analysis revealed that it was the normal haplotype that was lost. The findings provided a molecular explanation for the focal nature of cyst formation and a probable mechanism whereby mutations cause disease. The high rate at which 'second hits' must occur to account for the large number of cysts observed suggested to Qian et al. (1996) that unique structural features of the PKD1 gene may be responsible for its mutability. (This is a remarkable example of the Knudson mechanism which has been established in a considerable number of neoplasms. VAM.) They previously reported an extremely unusual 2.5-kb polypyrimidine tract within intron 21 of the PKD1 gene that they postulated as being responsible for the gene's increased rate of mutation (Burn et al., 1995). Qian et al. (1996) postulated that the polypyrimidine tract may cause ongoing errors in its transcription-coupled repair, thus resulting in a high frequency of somatic mutation. Thus, they concluded that PKD1 is a recessive disorder, when viewed at the level of the individual renal lesions. </p><p>Mutation screening of the PKD1 gene is complicated by the large transcript size (more than 14 kb) and by reiteration of the genomic area encoding 75% of the protein on the same chromosome. The sequence similarity between the duplicated region precludes specific analysis for mutations and consequently mutations were first identified in the unique 3-prime region of PKD1. Peral et al. (1997) developed a novel anchored RT-PCR approach to amplify specifically duplicated regions of PKD1, employing 1 primer situated within the single-copy region and 1 within the reiterated area. This strategy was incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22 to 46; 37% of the coding region), including 11 (exons 22 to 32) within the duplicated gene region, by use of the protein-truncation test (PTT). Sixty of the patients were also screened for missense changes, by use of the nonisotopic RNase cleavage assay (NIRCA), in exons 23 to 36. In this way, Peral et al. (1997) identified 11 mutations, 6 within the duplicated region: 3 stop mutations, 3 frameshifting deletions of 1 nucleotide, 2 splicing defects, and 3 possible missense changes. Each mutation was detected in just 1 family, although 1 had been described previously; no mutation hotspot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggested that the mutations may inactivate the molecule. Peral et al. (1997) recommended RT-PCR/PTT as a rapid and efficient method to detect PKD1 mutations and differentiate pathogenic changes from polymorphisms. </p><p>Constantinides et al. (1997) reported a new amino acid polymorphism, ala/val4058, with allelic frequencies of 0.88 and 0.12, respectively, and a heterozygosity of 0.23, in the Greek and Greek-Cypriot populations. The val4058 polymorphism occurred on the background of the ala4091-G allele of the ala4091-A/G polymorphism, previously described by Neophytou et al. (1996) and Peral et al. (1996). Neither polymorphism was observed in 44 Japanese subjects, leading Constantinides et al. (1997) to suggest that these polymorphic alleles would be useful for linkage analysis only in specific ethnic groups. </p><p>A major challenge faced by researchers attempting to do a complete mutation analysis of the PKD1 gene is the presence of several homologous loci, also located on chromosome 16. Because the sequence of PKD1 and its homologs is nearly identical in the 5-prime region of the gene, most traditional approaches to mutation analysis cannot distinguish sequence variants occurring uniquely in PKD1. Although linkage information indicates that mutations in PKD1 account for approximately 85% of all autosomal dominant PKD, relatively few mutations were identified in the 4-year period following the identification of the gene in 1994, and most were clustered in the unique portion of the gene. Approximately 70% of the length of the gene is present in at least 3 faithful copies at 16p13.1. The duplicated region extends from exon 1 to intron 34 and includes all intervening sequences. The PKD1 copies are transcribed but their respective mRNA molecules can be distinguished from authentic PKD1 transcripts on the basis of size. Furthermore, bisecting intron 21 of PKD1 is an unusual polypyrimidine tract of approximately 2.5 kb. This element is also present in the PKD1 homologs.</p><p>To study the duplicated region of PKD1, Watnick et al. (1997) devised a novel strategy that depends on long-range PCR and a single gene-specific primer from the unique region of the gene to amplify a PKD1-specific template that spans exons 23 to 34. This 10-kb template, amplified from genomic DNA, can be employed for mutation analysis using a wide range of sequence-based approaches. Using this long-range PCR strategy to screen for sequence variants with heteroduplex analysis, Watnick et al. (1997) identified several affected individuals with clusters of basepair substitutions in exons 23 and 25. In 2 patients, these changes, identified in exon 23, would be predicted to result in multiple amino acid substitutions in a short stretch of the protein. This unusual clustering of basepair substitutions suggested that mutation may result from unique structural features of the PKD1 gene. The observation that renal cysts are due to somatic mutations and the high frequency of 'second hits' implied by this in hereditary polycystic kidney disease also suggests an unusual mechanism of mutation. Watnick et al. (1997) observed that the PKD1 gene has 3 long polypyrimidine tracts within introns 1, 21, and 22, the longest of which is 2.5 kb in intron 21. The tract in intron 21 was the longest polypyrimidine tract sequenced to that time and contains 23 mirror repeats with stem lengths of at least 10 nucleotides. They predicted that the mirror repeats are likely to form H-DNA structures composed of a triple helix conformation under appropriate conditions. Triple helix structures can promote localized mutagenesis in cultured cells. The unusual pattern of clustered multiple basepair substitutions is consistent with that associated with triple helix formation. </p><p>Roelfsema et al. (1997) reduced the problem in mutation detection posed by the HG region by use of the protein-truncation test. They identified 8 novel mutations, 7 of which were located in the repeated part of the PKD1 gene (e.g., 601313.0008). </p><p>Watnick et al. (1997) devised a strategy for mutation detection in the duplicated region of PKD1. The method used 1 gene-specific primer, PKD1, as an anchor in combination with a primer from the duplicated portion to amplify PKD1-specific templates that are approximately 10 kb long and include exons 23 to 34 or exons 23 to 38. They demonstrated that the 3-prime long-range PCR product (3-prime-LR) is PKD1 specific once it has been diluted sufficiently to remove genomic contamination and could be used for nested PCR of any exon contained within it. These products could then be analyzed for PKD1 mutations with conventional methods such as heteroduplex or single-strand conformation polymorphism (SSCP) analysis. Using this technique, Watnick et al. (1997) identified an unusual cluster of nearly identical basepair transitions involving exon 23 in 2 unrelated individuals. These changes were predicted to result in multiple nonconservative amino acid substitutions in a short stretch of the protein. Both the unusual pattern of these mutations and their apparent independent origin prompted Watnick et al. (1998) to test whether these sequence differences could have arisen through gene conversion since pseudogenes had been known to be reservoirs for mutations by this mechanism for a number of other diseases, such as Gaucher disease and congenital adrenal hyperplasia due to 21-hydroxylase deficiency (201910). Using changes in restriction digest patterns, they showed that these sequence substitutions were also present in a rodent-human somatic cell hybrid that contained only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. Although PKD1 and CYP21, the gene mutant in congenital adrenal hyperplasia, resemble each other in some respects, they differ in the number and proximity of their homologous loci. The PKD1 gene is replicated in at least 3 copies that are located megabases away, while CYP21 has only 1 tandemly repeated unit. Multiple adjacent nucleotide substitutions have been described in the von Willebrand factor gene (VWF; 613160) on chromosome 12 that mimic the sequence of its pseudogene located on chromosome 22 (Eikenboom et al., 1994). Murti et al. (1994) demonstrated gene conversion between unlinked sequences in the germline of mice. Gene conversion, first studied extensively in yeast, is the nonreciprocal exchange of genetic information. Gene conversion and recombination may be related processes that involve pairing of homologous sequences except that in gene conversion, genetic information is transferred from the donor gene to the recipient without the donor being modified in the process. The fact that both PKD1 and its homologs contain unusual polypyrimidine tracts that are situated in adjacent introns may promote nonreciprocal recombination leading to gene conversion. They postulated that these polypyrimidine tracts form triple helices under appropriate conditions that could conceivably contribute to mutagenesis by more than 1 mechanism. Gene conversion may also account for the apparently high mutation rate, both somatic and germline, in the PKD1 gene. A high germline mutation is suggested by the frequency of polycystic kidney disease, which is estimated to be as high as 1 in 1,000 individuals, and by the high somatic mutation rate that is required, each with a separate second mutational event. It is possible, furthermore, that somatic mutation in the PKD1 gene represents the second hit in the case of the multiple cysts of PKD2 and PKD3 (Germino, 1998). </p><p>Thomas et al. (1999) concluded that when long-range PCR is applied to identify mutations in the duplicated part of the PKD1 gene, coupled with existing mutation detection methods, virtually the whole of this large, complex gene can be screened for mutations. By means of a PKD1-specific primer in intron 1, they used an approximately 13.6-kb PCR product that includes exons 2 to 15 of the PKD1 gene to search for mutations by direct sequence analysis. This region contains the majority of the predicted extracellular domains of the PKD1 gene product, polycystin, including the 16 novel PKD domains that have similarity to immunoglobulin-like domains found in many cell adhesion molecules and cell surface receptors. In 24 unrelated patients, 7 novel mutations were found: 2 deletions (1 of 3 kb and the other of 28 bp), 1 single-base insertion, and 4 nucleotide substitutions (1 splice site, 1 nonsense, and 2 missense). Five of these mutations were predicted to cause premature termination of the protein. Two coding and 18 silent polymorphisms were also found. </p><p>It is known that several of the most severe complications of autosomal dominant polycystic kidney disease, such as intracranial aneurysms, cluster in families. Watnick et al. (1999) described a cluster of 4 bp in exon 15 that is unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11 to 21 by use of long-range PCR. The 2 templates described were used to analyze 35 pedigrees selected for study because they included individuals with either intracranial aneurysms and/or very early-onset disease. Watnick et al. (1999) identified 8 novel truncating mutations, 2 missense mutations not found in a panel of controls, and several informative polymorphisms. Many of the polymorphisms were also present in the homologous loci on chromosome 16, supporting the idea that they may serve as a reservoir for genetic variability in the PKD1 gene. To their surprise, Watnick et al. (1999) found that 3 independently ascertained pedigrees had an identical 2-bp deletion in exon 15 (601313.0014). </p><p>Rossetti et al. (2001) developed methods to amplify all of the PKD1 coding area and screened for mutations in 131 unrelated patients with ADPKD, using the protein-truncation test and direct sequencing. Mutations were identified in 57 families, and, including 24 previously characterized changes from this cohort, a detection rate of 52.3% was achieved in 155 families. Mutations were distributed through all areas of the gene, from exon 1 to exon 46, with no clear hotspot identified. There was no significant difference in mutation frequency between the single-copy and duplicated areas of the gene, but mutations were more than twice as frequent in the 3-prime half of the gene, compared with the 5-prime half. Most mutations were predicted to truncate the protein through nonsense mutations (32%), insertions or deletions (29.6%), or splicing changes (6.2%), although the figures were biased by the methods employed, and, in sequenced areas, approximately 50% of all mutations were missense or in-frame. Other studies had suggested that gene conversion may be a significant cause of mutation in PKD1, but only 3 of 69 different mutations matched the PKD1-like HG sequence. A relatively high rate of new PKD1 mutations was calculated, 1.8 x 10(-5) mutations per generation, consistent with the many different mutations identified (69 in 81 pedigrees) and suggesting significant selection against mutant alleles. In this study, the mutation detection rate of more than 50% was comparable to that achieved for other large multiexon genes and showed the feasibility of DNA diagnosis in this disorder. </p><p>Perrichot et al. (1999) used denaturing gradient gel electrophoresis (DGGE) to scan for mutations in the nonduplicated region of the PKD1 gene in a large cohort of 146 French unrelated ADPKD patients. They identified several novel mutations: 3 frameshift mutations, 2 nonsense mutations, 2 missense mutations, 1 insertion in a frame of 9 nucleotides, 3 intronic variations, and several polymorphisms. One of these mutations, W4139X (601313.0015), was said by Perrichot et al. (1999) to be the fourth reported de novo mutation in the PKD1 gene. Anticipation was suspected in 1 family in which the diagnosis was made in utero in a member of the most recent generation. This study was undertaken in patients in Brittany, a Celtic area in the western part of France. A previous epidemiologic study in Brittany by Simon et al. (1996) found the frequency of the disease to be close to 1 in 1,100. </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 the PKD1 gene was of germinal nature and the mutation in the PKD2 gene was of somatic nature. The authors stated that to their knowledge this was the first demonstration of the transheterozygous model as a mechanism for human disease development. In Drosophila melanogaster, a transheterozygous situation for 2 recessive mutations, the multiple wing hair and flare-3, has been exploited by Delgado-Rodriguez et al. (1999) for developing the wing spot test, which identifies genotoxic substances. </p><p>Koptides and Deltas (2000) reviewed the molecular genetics and molecular pathogenesis of ADPKD. They reviewed data that support or possibly contradict the 2-hit hypothesis, and other data that support the transheterozygous model for cystogenesis. </p><p>Using exon-by-exon SSCP analysis on long-range PCR products, Bouba et al. (2001) performed a systematic screening of part of the duplicated region of the PKD1 gene in a cohort of 53 Hellenic ADPKD families from Greece and Cyprus. The region screened (exons 16-34) represented 23% of the PKD1 coding sequence, and 8 probable disease mutations were identified: 5 deletions and 3 missense mutations. In one family, a 3-bp and an 8-bp deletion in exons 20 and 21, respectively, were coinherited on the same PKD1 chromosome, causing disease in the mother and 3 sons. Eleven intragenic polymorphisms were also detected, representing neutral or coding variants, confirming previous suggestions that the PKD1 gene is prone to mutations. </p><p>Pei et al. (2001) reported studies of an extensively affected Newfoundland family in which it appeared that there was bilineal polycystic kidney disease from independently segregating PKD1 and PKD2 mutations. Affected members who were heterozygous for mutations in both the PKD1 and PKD2 genes (transheterozygotes) had a more severe clinical course than those with mutations in only 1 of the genes. </p><p>In 17 unrelated Australian individuals with PKD1-linked autosomal dominant PKD, McCluskey et al. (2002) screened for disease-causing mutations in the duplicated region of the PKD1 gene. They identified 12 novel probably pathogenic DNA variants. Defects in the duplicated region of the gene accounted for 63% of the patients. Together with the previously detected mutations in the 3-prime region of the gene, the study achieved an overall mutation detection rate of 74%. They also detected 31 variants (9 novel and 22 previously published) that did not segregate with the disease and were considered to be polymorphisms. Three of the 9 novel polymorphisms were missense mutations with a predicted effect on protein conformation, emphasizing the problems of interpretation in PKD1 mutation screening. </p><p>Inoue et al. (2002) examined PKD1 mutations in Japanese ADPKD patients. Six novel chain-terminating mutations were detected. They concluded that most PKD1 mutations in Japanese ADPKD patients are novel and definitely pathogenic. One pedigree did not link to either PKD1 or PKD2. </p><p>Eo et al. (2002) described 3 novel mutations of the PKD1 gene in Korean patients. In this study, the clinical data from affected individuals and from previously reported Korean PKD1 mutations showed that patients with frameshift or nonsense mutations were more prone to develop end-stage renal failure than those with missense mutations. </p><p>Familial clustering of intracranial aneurysms suggests that genetic factors are important in the etiology of ADPKD. Rossetti et al. (2003) characterized mutations in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and 7 were PKD2 (12%). The median position of the PKD1 mutation was significantly further 5-prime in the vascular population than in the 87 control pedigrees (amino acid position 2163 vs 2773, p = 0.0034). Subsets of the vascular population with aneurysmal rupture, early rupture, or families with more than 1 vascular case had median mutation locations even further 5-prime. </p><p>Gout et al. (2007) retrospectively reviewed published variants in the PKD1 genes and detected errors in 39 of 771 variants (5.06%). All arose from human processing mistakes. As peer-reviewed publication is no safeguard for those considering the clinical significance of an unknown variant, the authors suggested that reporting of new variants for the proposed Human Variome Project should employ both automated reporting and expert scrutiny. Errors were grouped into 3 categories: misassignment, miscounting, and typographical. A table of erroneous variant reports with corrections was published. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</h4>
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<p>Himmelbauer et al. (1991, 1992) mapped 2 human cDNA clones, derived from the region between markers flanking PKD1, in the mouse genome. From the study of recombinant inbred strains and of somatic cell hybrids, they found that the PKD1 region markers mapped to mouse chromosome 17. </p><p>Aziz et al. (1993, 1994) demonstrated that the mouse Ke6 gene (601417) is involved in the manifestation of polycystic kidney disease in 2 different murine models of PKD. The HKE4 (601416) and HKE6 genes are located in the major histocompatibility complex in mouse and human, on mouse chromosome 17 and human chromosome 6, respectively. </p><p>Olsson et al. (1996) mapped the Pkd1 locus to mouse chromosome 17 using somatic cell hybrids, B x D recombinant inbred strains, and fluorescence in situ hybridization. The gene is located within a previously defined conserved synteny group that includes the mouse homolog of tuberous sclerosis-2 (TSC2; 191092) and is linked to the alpha-globin pseudogene. Like their human counterparts, the mouse Tsc2 and Pkd1 genes are arranged in a tail-to-tail orientation with a distance of only 63 bp between the polyadenylation signals of the 2 genes. </p><p>Lohning et al. (1997) studied the mouse version of the PKD1 gene. The predicted protein is 79% identical to human PKD1 and contains most of the domains identified in the human sequence. As in the human, the mouse homolog is transcribed from a unique gene and there are no transcribed, closely related copies. At the junction of exons 12 and 13, several different splicing variants were identified that lead to a predicted protein that could be secreted. These forms were found predominantly in newborn brain, while in kidney the transcript homologous to the previously described human RNA predominated. </p><p>Lu et al. (1997) introduced into mice by homologous recombination a Pkd1 truncation mutation that mimicked a mutation found in human ADPKD. Heterozygotes had no discernible phenotype, whereas homozygotes died during the perinatal period with massively enlarged cystic kidneys, pancreatic ductal cysts, and pulmonary hypoplasia. Renal cyst formation began at embryonic day 15.5 in proximal tubules and progressed rapidly to replace the entire renal parenchyma. The timing of cyst formation suggested that full-length polycystin is required for normal morphogenesis during elongation and maturation of tubular structures in the kidney and pancreas. Hepatic and pancreatic cysts are rather common in ADPKD (Gabow, 1993), but are rarely of clinical significance. The pulmonary hypoplasia that occurred in the mice and is found in polycystic disease in childhood probably results from oligohydramnios and abdominal distention produced by renal enlargement. Although liver cysts occur in about 30% of patients with ADPKD, surprisingly none were observed in the homozygous mutant mice. There were also no abnormalities in tissues such as myocardium and vascular smooth muscle in which polycystin is normally expressed. These findings suggested that vascular abnormalities such as aneurysm may be secondary phenomena, and indeed these have been commonly attributed to the occurrence of hypertension. However, Kim et al. (2000) demonstrated a primary role of PKD1 mutations in vascular fragility. They found that mouse embryos homozygous for a mutant allele, generated by knockout, exhibited subcutaneous edema, vascular leaks, and rupture of blood vessels, culminating in lethality at embryonic day 15.5. Kidney and pancreatic ductal cysts were present. They detected mouse polycystin-1 in normal endothelium and the surrounding vascular smooth muscle cells. These data revealed a requisite role for polycystin-1 in maintaining the structural integrity of the vasculature as well as epithelium and suggested that the nature of the PKD1 mutation contributes to the phenotypic variance in ADPKD. </p><p>Pritchard et al. (2000) generated transgenic mice with approximately 30 copies of a 108-kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease gene, PKD1. Two such cell lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life that was markedly reduced at the conclusion of renal development. Transgenic animals from both lines often displayed multiple renal microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. To test the functionality of the transgene, animals were bred with the Pkd1del34 knockout mouse (Lu et al., 1997). Both transgenic lines rescued the embryonically lethal Pkd1del34/del34 phenotype, demonstrating that human polycystin-1 can compensate for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1del34/+ animals. The authors hypothesized that overexpression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease. </p><p>Kleymenova et al. (2001) found that rats with a germline inactivation of 1 allele of the Tsc2 tumor suppressor gene developed early-onset severe bilateral polycystic kidney disease, with similarities to the human contiguous gene syndrome caused by germline codeletion of the PKD1 and TSC2 genes. Polycystic rat renal cells retained 2 normal Pkd1 alleles but were null for Tsc2 and exhibited loss of lateral membrane-localized polycystin-1. In tuberin-deficient cells, intracellular trafficking of polycystin-1 was disrupted, resulting in sequestration of polycystin-1 within the Golgi, and reexpression of Tsc2 restored correct polycystin-1 membrane localization. These data identified tuberin as a determinant of polycystin-1 functional localization and, potentially, autosomal dominant polycystic kidney disease severity. </p><p>Boulter et al. (2001) described mice carrying a targeted mutation in the Pkd1 gene, which defined its expression pattern by using a lacZ reporter gene. Although heterozygous adult mice developed renal and hepatic cysts, homozygous embryos died at embryonic days 13.5 to 14.5 from a primary cardiovascular defect that included double outflow right ventricle, disorganized myocardium, and abnormal atrioventricular septation. Skeletal development was also severely compromised. These abnormalities correlated with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 was expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincided with the onset of cyst formation in transgenic mice for mutations either in Pkd1 or Pkd2, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function. </p><p>Lu et al. (2001) reported the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a truncation mutation in Pkd1. Null homozygotes develop more aggressive renal and pancreatic cystic disease than del34/del34. Moreover, both homozygous mutants developed polyhydramnios, hydrops fetalis, spina bifida occulta, and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. The del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the 2-hit model. The authors concluded that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and polycystin-1 may be critical in both epithelium and chondrocyte development. </p><p>To study molecular defects in Pkd1 mutants, Muto et al. (2002) generated a mouse with a targeted deletion of exons 2 to 6 of Pkd1. Homozygous embryos (Pkd1 -/-) developed hydrops, cardiac conotruncal defects, and renal cystogenesis. Total protein levels of beta-catenin in heart and kidney and c-myc (190080) in heart were decreased in Pkd1 -/- embryos. In the kidneys of Pkd1 -/-, the expression of E-cadherin and Pecam1 (173445) in basolateral membranes of renal tubules was attenuated, and tyrosine phosphorylation of Egfr (131550) and Gab1 (604439) were constitutively enhanced when cystogenesis started on embryonic day 15.5 to 16.5. Maternally administered pioglitazone, a thiazolidinedione compound, resolved these molecular defects of Pkd1 -/-. Treatment with pioglitazone improved survival of Pkd1 -/- embryos and ameliorated the cardiac defects and the degree of renal cystogenesis. Long-term treatment with pioglitazone improved the endothelial function of adult Pkd1 +/-. The authors concluded that molecular defects observed in Pkd1 -/- embryos contributed to the pathogenesis of ADPKD, and that thiazolidinediones had a compensatory effect on the pathway affected by the loss of polycystin-1. </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 suggested a contribution from threshold effects to cyst formation and growth. </p><p>Lantinga-van Leeuwen et al. (2004) generated mice carrying a hypomorphic Pkd1 allele (Pkd1nl), which yielded only 13 to 20% normally spliced Pkd1 transcripts in homozygous mice. Homozygous Pkd1nl mice were viable, showing bilaterally enlarged polycystic kidneys. In addition, homozygous Pkd1nl mice showed dilatations of pancreatic and liver bile ducts as well as cardiovascular abnormalities, pathogenic features similar to the human ADPKD phenotype. The authors concluded that a reduced dosage of Pkd1 is sufficient to initiate cystogenesis and vascular defects, and that low Pkd1 gene expression levels can overcome the embryonic lethality seen in Pkd1-knockout mice. Lantinga-van Leeuwen et al. (2004) hypothesized that in patients, reduced PKD1 expression of the normal allele below a critical level, due to genetic, environmental, or stochastic factors, may lead to cyst formation in the kidneys and other clinical features of ADPKD. </p><p>The homolog of the human PKD1 gene maps to feline chromosome E3. Young et al. (2005) demonstrated that the feline polycystic kidney disease maps to this region. </p><p>Piontek et al. (2007) found that inactivation of the Pkd1 gene in mice before postnatal day 13 resulted in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 or later resulted in cysts only after 5 months. In both cases, the cysts originated from all tubular segments. The abrupt change in response to Pkd1 inactivation corresponded to a brake point in renal growth and significant changes in gene expression. Piontek et al. (2007) concluded that the pathologic consequences of PKD1 inactivation are defined by a developmental switch that signals terminal renal maturation. </p><p>Patients with tuberous sclerosis often develop renal cysts and those with inherited codeletions of PKD1 gene develop severe, early-onset polycystic kidneys. Using mouse models, Bonnet et al. (2009) showed that many of the earliest lesions from Tsc1 (605284) +/-, Tsc2 +/-, and Pkd1 +/- mice did not exhibit activation of mTOR, confirming an mTOR-independent pathway of renal cystogenesis. Using Tsc1/Pkd1 and Tsc2/Pkd1 heterozygous double-mutants, the authors showed functional cooperation and an effect on renal primary cilium length between hamartin and tuberin with polycystin-1. The Tsc1, Tsc2, and Pkd1 gene products helped regulate primary cilia length in renal tubules, renal epithelial cells, and precystic hepatic cholangiocytes. Consistent with the function of cilia in modulating cell polarity, Bonnet et al. (2009) found that many dividing precystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2, and Pkd1 heterozygous mice were highly misoriented. Bonnet et al. (2009) proposed that defects in cell polarity may underlie cystic disease associated with TSC1, TSC2, and PKD1, and that targeting of this pathway may be of key therapeutic benefit. </p><p>Takakura et al. (2009) showed that renal injury led to massive cystic disease in a mouse model of adult inactivation of Pkd1 using the Mx1Cre(+) allele. Cysts were labeled with a collecting duct/tubule marker Dolichos biflorus agglutinin, which correlated with the site of Cre-mediated recombination in the collecting system. BrdU labeling revealed that cyst-lining epithelial cells were composed of regenerated cells in response to renal injury. Takakura et al. (2009) proposed a role for polycystin-1 in kidney injury and repair and suggested that renal injury may constitute a 'third hit' resulting in rapid cyst formation in adulthood. </p><p>Kurbegovic et al. (2010) generated 3 transgenic mouse lines from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wildtype genomic Pkd1 expression within the native tissue and temporal regulation. The mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from 2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Pkd1(TAG) mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis, as is frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and approximately 15% intrahepatic cysts of the bile ducts, affecting females preferentially. A significant proportion of mice developed cardiac anomalies with severe left ventricular hypertrophy, marked aortic arch distention, and/or valvular stenosis and calcification that had profound functional impact. Pkd1(TAG) mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. </p><p>Using a combination of targeted knockout and overexpression with 2 genes mutated in polycystic liver disease (PCLD1, 174050; PCLD2, 617004), Prkcsh (177060) and Sec63 (608648), respectively, 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>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 (604683) 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, or cAMP. </p>
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<strong>History</strong>
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<p>Chanmugam et al. (1971) reported a family that might suggest linkage of hereditary spherocytosis (see 182900) and polycystic kidney disease. A father and 3 children had both diseases. Three other children and 4 sibs of the father were thought to be free of both diseases. There is, however, no other suggestion of location of a spherocytosis locus on chromosome 16, or chromosome 4 (cf. 173910), where genes for adult polycystic kidney disease have been mapped. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>16 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, IVSDS, G-C, +1
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<br />
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SNP: rs2151684070,
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ClinVar: RCV000008678
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<p>In probands with polycystic kidney disease-1 (PKD1; 173900), the European Polycystic Kidney Disease Consortium (1994) found 4 mutations in the PKD1 gene, including a G-to-C transition at position +1 of the splice donor site following the 135-bp exon and resulting in an in-frame deletion of basepairs 3696-3831. The proband was from a large family in which the disease could be traced through 3 generations. In a parent and 2 affected sibs, the abnormal transcript segregated with PKD1. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, GLN1273TER
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SNP: rs199476094,
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ClinVar: RCV000008679, RCV000681743
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<p>Turco et al. (1995) used PCR with primer pairs located in the 3-prime unique region of the PKD1 gene and heteroduplex DNA analysis in 20 unrelated ADPKD probands (PKD1; 173900) from northern Italy, all of whom were members of families in which previous studies had indicated linkage to PKD1. In 5 affected individuals from the same family, they found novel aberrant bands that were absent in 13 unaffected family members. Cloning and automated DNA sequencing revealed a C-to-T transition at nucleotide 3817 of the published cDNA sequence, which created a premature stop codon. The mutation changed a CAG codon for glutamine to a TAG amber stop codon (Q1273X). The mutation destroyed an MspA1I restriction site, and the abnormal restriction pattern was observed on genomic DNA from all the affected family members. RT-PCR and restriction analysis performed on peripheral white blood cell mRNA showed that in the affected members both the mutant and the normal transcript were represented. The mutation was not found in the probands of the other families studied. This appears to have been the first nonsense mutation described in the PKD1 gene. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 POLYCYSTIC KIDNEY DISEASE 1</strong>
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PKD1, 15-BP DEL
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SNP: rs1567154953,
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ClinVar: RCV000008680
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<p>Among the 6 novel mutations in families with polycystic kidney disease (PDK1; 173900) identified by Peral et al. (1996) was an in-frame 15-bp deletion that removed 5 amino acids, RQVRL, between amino acids 3747 and 3753. The deletion was probably promoted by misalignment of 2 directly repeated 7-bp sequences. The repeated sequences meant that the precise region deleted could not be determined. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 POLYCYSTIC KIDNEY DISEASE 1</strong>
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</span>
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PKD1, ARG4227TER
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SNP: rs199476095,
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gnomAD: rs199476095,
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ClinVar: RCV000008681, RCV000788852
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<span class="mim-text-font">
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<p>Peral et al. (1996) found an abnormal fragment by SSCP analysis of the PKD1 gene in a patient with polycystic kidney disease (PKD1; 173900). Direct sequencing revealed a C-to-T transition changing the arg4227 codon, CGA, to a stop codon, TGA, and giving rise to a predicted truncated protein 76 amino acids shorter than the normal protein. The same abnormality was found in 2 affected relatives. </p>
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</div>
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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PKD1, GLN3837TER
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<br />
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|
|
|
SNP: rs199476096,
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|
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|
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ClinVar: RCV000008682, RCV002293410
|
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|
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|
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</span>
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|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>Peral et al. (1996) used SSCP analysis followed by direct sequencing in a patient with polycystic kidney disease (PKD1; 173900) revealed a gln3837-to-ter (CAG-to-TAG, Q3837X) mutation in the PKD1 gene. The mutation abolished a PvuII restriction site and this was used to confirm the mutation in 2 other affected relatives. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
|
|
</div>
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|
|
</div>
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|
<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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PKD1, CYS4086TER
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<br />
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|
SNP: rs199476097,
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|
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ClinVar: RCV000008683
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|
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|
</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large Cypriot family with polycystic kidney disease (PKD1; 173900), Neophytou et al. (1996) identified a T-to-A nucleotide substitution at position 12258 in the 3-prime region of the PKD1 gene that led to a cys4086-to-ter mutation (C4086X). The premature stop codon is expected to remove 217 amino acids from the C-terminal intracellular domain of the gene product. </p>
|
|
</span>
|
|
</div>
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|
<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, TYR3818TER
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|
<br />
|
|
|
|
SNP: rs199476098,
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|
|
|
|
|
gnomAD: rs199476098,
|
|
|
|
|
|
ClinVar: RCV000008684, RCV003993740
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Peral et al. (1996) described a tyr3818-to-ter (Y3818X) mutation in the PKD1 gene in a severely affected child with polycystic kidney disease (PKD1; 173900). They found the same mutation in her clinically normal twin brother and in her father who had typical adult-onset disease. Because the same stable mutation was associated with very different disease severity in this family, Peral et al. (1996) proposed that a small number of modifying factors may radically affect the course of type 1 polycystic kidney disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, 12036G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1218054241,
|
|
|
|
|
|
gnomAD: rs1218054241,
|
|
|
|
|
|
ClinVar: RCV000008685, RCV003162219
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In individuals of Dutch origin with autosomal dominant polycystic kidney disease (PKD1; 173900), Roelfsema et al. (1997) used the protein truncation test (PTT) to detect mutations in the PKD1 gene. Since the PTT detects only translation-terminating mutations, all mutations that they found were either base substitutions leading to a stop codon or frameshifts. In 4 cases there were small deletions leading to frameshifts; base substitutions were found in 3 individuals. One of these was a G-to-A transition of nucleotide 12036 in exon 44. The transition created a new Sau3AI restriction site and eliminated an AvaII site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, 28-BP DEL, NT6434
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1567192790,
|
|
|
|
|
|
|
|
ClinVar: RCV000008686
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using long-range PCR and direct sequence analysis in a group of 24 unrelated patients with autosomal dominant polycystic kidney disease (173900), Thomas et al. (1999) identified 7 novel mutations in the PKD1 gene, one of which was a 28-bp deletion involving nucleotides 6434-6461 in exon 15. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, IVS14AS, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1567204631,
|
|
|
|
|
|
|
|
ClinVar: RCV000008687
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>One of 7 unique mutations identified by Thomas et al. (1999) in patients with polycystic kidney disease (PKD1; 173900) was a splice mutation, a G-to-A transition at position -1 in the acceptor site in intron 14. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, ARG324LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199476099,
|
|
|
|
|
|
gnomAD: rs199476099,
|
|
|
|
|
|
ClinVar: RCV000008688, RCV000756490, RCV001292035, RCV003150927, RCV003924816
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>One of 7 unique mutations identified by Thomas et al. (1999) by long-range PCR and direct sequencing of the PKD1 gene in patients with polycystic kidney disease (PKD1; 173900) was an arg324-to-leu (R324L) mutation in exon 5. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, LEU845SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199476100,
|
|
|
|
|
|
gnomAD: rs199476100,
|
|
|
|
|
|
ClinVar: RCV000008689, RCV000712602, RCV000761309, RCV001292482, RCV004739297
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>One of 7 unique mutations identified by Thomas et al. (1999) by long-range PCR and direct sequencing of the PKD1 gene in patients with polycystic kidney disease (PKD1; 173900) was a leu845-to-ser (L845S) mutation in exon 11. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, GLN1922TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199476101,
|
|
|
|
|
|
|
|
ClinVar: RCV000008690
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>One of 7 unique mutations identified by Thomas et al. (1999) by long-range PCR and direct sequencing of the PKD1 gene in patients with polycystic kidney disease (PKD1; 173900) was a nonsense mutation, gln1922 to ter (Q1922X), in exon 15. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 POLYCYSTIC KIDNEY DISEASE 1, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, 2-BP DEL, 5224AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555455457,
|
|
|
|
|
|
|
|
ClinVar: RCV000518367, RCV000989457, RCV001292374, RCV001813786, RCV004023518, RCV004740299
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 of 35 independently ascertained pedigrees with polycystic kidney disease (PKD1; 173900) selected for study because they included individuals with either intracranial aneurysms and/or very early-onset disease, Watnick et al. (1999) identified an identical 2-bp deletion (AG) at nucleotide 5224 in exon 15 of the PKD1 gene. One family contained an individual with a cerebral aneurysm. A second family was evaluated because a child had very early-onset disease; the affected father had the same mutation as the daughter. The third family had at least 3 individuals with aneurysms, including 1 with very early onset. There were 2 additional individuals in this family (both cousins of the individual with both early onset-disease and aneurysm) who had very early-onset disease but from whom DNA samples were not available. Although each of these 3 families had individuals who were severely affected, there were also individuals with renal cystic disease and a more routine presentation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 POLYCYSTIC KIDNEY DISEASE 1, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, TRP4139TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199476102,
|
|
|
|
|
|
|
|
ClinVar: RCV000008692, RCV004783721
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 25-year-old French patient with autosomal dominant polycystic kidney disease (PKD1; 173900), Perrichot et al. (1999) identified what they claimed to be the fourth reported de novo mutation in the PKD1 gene: a 12628G-A transition in exon 45 leading to a trp4139-to-ter (W4139X) mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 POLYCYSTIC KIDNEY DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PKD1, 3-BP DEL, EX20 AND 8-BP DEL, EX21
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2151766716, rs748240352,
|
|
|
|
|
|
gnomAD: rs748240352,
|
|
|
|
|
|
ClinVar: RCV000008693, RCV005054409
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with autosomal dominant polycystic kidney disease (PKD1; 173900), Bouba et al. (2001) identified 2 deletions in the PKD1 gene: a 3-bp deletion in exon 20 and an 8-bp deletion in exon 21. The deletions were coinherited on the same chromosome, causing disease in the mother and 3 sons. The 3-bp mutation corresponded to glycine at codon 2579. The 8-bp deletion was predicted to result in a translation frameshift after amino acid 2657, leading to a stop codon 483 bp downstream. Cloning and sequencing experiments showed that the 2 deletions were in cis position on the chromosome that was inherited from the affected mother. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B.
|
|
<strong>Down-regulation of Ke6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease.</strong>
|
|
Molec. Cell. Biol. 13: 1847-1853, 1993. Note: Erratum: Molec. Cell. Biol. 13: 6614 only, 1993.
|
|
|
|
|
|
[PubMed: 8441417]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/mcb.13.3.1847-1853.1993]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B.
|
|
<strong>Coordinate regulation of 11-beta-HSD and Ke6 gene in cpk mouse: implications for steroid metabolic defect in PKD.</strong>
|
|
Am. J. Physiol. 267: F791-F797, 1994.
|
|
|
|
|
|
[PubMed: 7977782]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1152/ajprenal.1994.267.5.F791]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bear, J. C., McManamon, P., Morgan, J., Payne, R. H., Lewis, H., Gault, M. H., Churchill, D. N.
|
|
<strong>Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling.</strong>
|
|
Am. J. Med. Genet. 18: 45-53, 1984.
|
|
|
|
|
|
[PubMed: 6741995]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.1320180108]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bear, J. C., Parfrey, P. S., Morgan, J. M., Martin, C. J., Cramer, B. C.
|
|
<strong>Autosomal dominant polycystic kidney disease: new information for genetic counselling.</strong>
|
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Am. J. Med. Genet. 43: 548-553, 1992.
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<strong>A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family.</strong>
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Hum. Molec. Genet. 4: 1331-1335, 1995.
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[PubMed: 7581371]
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[Full Text: https://doi.org/10.1093/hmg/4.8.1331]
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Ward, C. J., Turley, H., Ong, A. C. M., Comley, M., Biddolph, S., Chetty, R., Ratcliffe, P. J., Gatter, K., Harris, P. C.
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<strong>Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney.</strong>
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Proc. Nat. Acad. Sci. 93: 1524-1528, 1996.
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[PubMed: 8643665]
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[Full Text: https://doi.org/10.1073/pnas.93.4.1524]
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Watnick, T. J., Gandolph, M. A., Weber, H., Neumann, H. P. H., Germino, G. G.
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<strong>Gene conversion is a likely cause of mutation in PKD1.</strong>
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Hum. Molec. Genet. 7: 1239-1243, 1998.
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[PubMed: 9668165]
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[Full Text: https://doi.org/10.1093/hmg/7.8.1239]
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Watnick, T. J., Piontek, K. B., Cordal, T. M., Weber, H., Gandolph, M. A., Qian, F., Lens, X. M., Neumann, H. P. H., Germino, G. G.
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<strong>An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.</strong>
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Hum. Molec. Genet. 6: 1473-1481, 1997.
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[PubMed: 9285784]
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[Full Text: https://doi.org/10.1093/hmg/6.9.1473]
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Watnick, T. J., Torres, V. E., Gandolph, M. A., Qian, F., Onuchic, L. F., Klinger, K. W., Landes, G., Germino, G. G.
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<strong>Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease.</strong>
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Molec. Cell 2: 247-251, 1998.
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[PubMed: 9734362]
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[Full Text: https://doi.org/10.1016/s1097-2765(00)80135-5]
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<li>
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<p class="mim-text-font">
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Watnick, T., Phakdeekitcharoen, B., Johnson, A., Gandolph, M., Wang, M., Briefel, G., Klinger, K. W., Kimberling, W., Gabow, P., Germino, G. G.
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<strong>Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.</strong>
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Am. J. Hum. Genet. 65: 1561-1571, 1999.
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[PubMed: 10577909]
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[Full Text: https://doi.org/10.1086/302657]
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</p>
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<p class="mim-text-font">
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Watson, M. L., Wright, A. F., Macnicol, A. M., Allan, P. L., Clayton, J. F., Dempster, M., Jeremiah, S. J., Corney, G., Hopkinson, D. A.
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<strong>Studies of genetic linkage between adult polycystic kidney disease and three markers on chromosome 16.</strong>
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J. Med. Genet. 24: 457-461, 1987.
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[PubMed: 2821260]
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[Full Text: https://doi.org/10.1136/jmg.24.8.457]
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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: 12140187]
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[Full Text: https://doi.org/10.1093/hmg/11.16.1845]
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Wunderle, V., Ramkissoon, Y. D., Kwok, C., Korn, R. M., King, V. E., Goodfellow, P. N.
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<strong>Breakpoint break for consortium studying adult polycystic kidney disease.</strong>
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Cell 77: 785-786, 1994.
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[PubMed: 8004666]
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[Full Text: https://doi.org/10.1016/0092-8674(94)90123-6]
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Xu, G. M., Sikaneta, T., Sullivan, B. M., Zhang, Q., Andreucci, M., Stehle, T., Drummond, I., Arnaout, M. A.
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<strong>Polycystin-1 interacts with intermediate filaments.</strong>
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J. Biol. Chem. 276: 46544-46552, 2001.
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[PubMed: 11581269]
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[Full Text: https://doi.org/10.1074/jbc.M107828200]
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Young, A. E., Biller, D. S., Herrgesell, E. J., Roberts, H. R., Lyons, L. A.
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<strong>Feline polycystic kidney disease is linked to the PKD1 region.</strong>
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Mammalian Genome 16: 59-65, 2005.
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[PubMed: 15674734]
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Zerres, K., Rudnik-Schoneborn, S., Deget, F., Beetz, R., Brodehl, J., Kuwertz-Broking, E., Muller-Wiefel, D., Rascher, W., Ruder, H., Scharer, K., Weber, H. P.
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[PubMed: 8411032]
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[Full Text: https://doi.org/10.1136/jmg.30.7.583]
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Ada Hamosh - updated : 11/20/2018<br>Patricia A. Hartz - updated : 1/15/2014<br>George E. Tiller - updated : 11/14/2011<br>Patricia A. Hartz - updated : 8/10/2011<br>George E. Tiller - updated : 4/1/2010<br>George E. Tiller - updated : 4/1/2010<br>George E. Tiller - updated : 3/30/2010<br>George E. Tiller - updated : 3/3/2010<br>Patricia A. Hartz - updated : 12/10/2009<br>Patricia A. Hartz - updated : 1/25/2008<br>Victor A. McKusick - updated : 6/8/2007<br>George E. Tiller - updated : 5/21/2007<br>Patricia A. Hartz - updated : 6/2/2006<br>Patricia A. Hartz - updated : 4/7/2006<br>Patricia A. Hartz - updated : 2/8/2006<br>Patricia A. Hartz - updated : 6/2/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Marla J. F. O'Neill - updated : 1/19/2005<br>Patricia A. Hartz - updated : 1/18/2005<br>Victor A. McKusick - updated : 2/2/2004<br>Victor A. McKusick - updated : 12/23/2003<br>George E. Tiller - updated : 6/19/2003<br>Victor A. McKusick - updated : 2/3/2003<br>Victor A. McKusick - updated : 1/13/2003<br>George E. Tiller - updated : 12/4/2002<br>Victor A. McKusick - updated : 11/25/2002<br>Patricia A. Hartz - updated : 10/29/2002<br>George E. Tiller - updated : 9/18/2002<br>Patricia A. Hartz - updated : 7/1/2002<br>Victor A. McKusick - updated : 6/14/2002<br>George E. Tiller - updated : 5/2/2002<br>Stylianos E. Antonarakis - updated : 5/1/2002<br>Victor A. McKusick - updated : 4/4/2002<br>Michael B. Petersen - updated : 2/28/2002<br>Victor A. McKusick - updated : 10/29/2001<br>Stylianos E. Antonarakis - updated : 8/7/2001<br>George E. Tiller - updated : 1/29/2001<br>Victor A. McKusick - updated : 1/24/2001<br>Stylianos E. Antonarakis - updated : 12/14/2000<br>George E. Tiller - updated : 10/17/2000<br>Victor A. McKusick - updated : 9/14/2000<br>Victor A. McKusick - updated : 2/2/2000<br>Victor A. McKusick - updated : 12/17/1999<br>Victor A. McKusick - updated : 12/7/1999<br>Victor A. McKusick - updated : 6/28/1999<br>Stylianos E. Antonarakis - updated : 12/23/1998<br>Victor A. McKusick - updated : 8/3/1998<br>Victor A. McKusick - updated : 11/26/1997<br>Victor A. McKusick - updated : 9/30/1997<br>Victor A. McKusick - updated : 9/22/1997<br>Victor A. McKusick - updated : 8/12/1997<br>Victor A. McKusick - updated : 7/14/1997<br>Ada Hamosh - updated : 7/10/1997<br>Victor A. McKusick - updated : 6/26/1997<br>Victor A. McKusick - updated : 6/17/1997<br>Victor A. McKusick - updated : 6/2/1997<br>Moyra Smith - updated : 9/11/1996<br>Moyra Smith - updated : 8/27/1996
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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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