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Entry
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- *602676 - PHOSPHODIESTERASE 6D; PDE6D
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- OMIM
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<p>
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<span class="h4">*602676</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602676">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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 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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<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 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=ENSG00000156973;t=ENST00000287600" 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=5147" 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=602676" 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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<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=ENSG00000156973;t=ENST00000287600" 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_001291018,NM_002601,NR_110994,XM_047444726" 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_002601" 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=602676" 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 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=04056&isoform_id=04056_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/PDE6D" 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/2655094,2896020,3294553,4505671,5921809,14043741,30583395,48146077,62988764,119591383,119591384,597518021,2217328783,2462574214" 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/O43924" 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=5147" 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=ENSG00000156973;t=ENST00000287600" 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=PDE6D" 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=PDE6D" 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+5147" 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/PDE6D" 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:5147" 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/5147" 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=chr2&hgg_gene=ENST00000287600.9&hgg_start=231732433&hgg_end=231781282&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 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602676[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=602676[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000156973" 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=PDE6D" 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=PDE6D" 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=PDE6D" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PDE6D&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/PA33136" 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:8788" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0032059.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1270843" 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/PDE6D#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:1270843" 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/5147/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5147" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003966;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040718-463" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5147" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=PDE6D&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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602676
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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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PHOSPHODIESTERASE 6D; PDE6D
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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">
|
|
PHOSPHODIESTERASE 6D, cGMP-SPECIFIC, ROD, DELTA<br />
|
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RETINAL ROD PHOTORECEPTOR cGMP PHOSPHODIESTERASE, DELTA SUBUNIT; PDED<br />
|
|
PDE-DELTA
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PDE6D" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PDE6D</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/2/1104?start=-3&limit=10&highlight=1104">2q37.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:231732433-231781282&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'})">2:231,732,433-231,781,282</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/2/1104?start=-3&limit=10&highlight=1104">
|
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2q37.1
|
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</a>
|
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</span>
|
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</td>
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|
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<td>
|
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<span class="mim-font">
|
|
Joubert syndrome 22
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/615665"> 615665 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/602676" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/602676" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
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<p>PDE6D is a phosphodiesterase (<a href="https://enzyme.expasy.org/EC/3.1.4.17" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.1.4.17</a>) that binds to prenyl groups and has a critical role in ciliogenesis (<a href="#4" class="mim-tip-reference" title="Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C., Seo, S. <strong>ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting.</strong> Proc. Nat. Acad. Sci. 109: 19691-19696, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150559[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.1210916109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150559">Humbert et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23150559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Ershova, G., Derre, J., Chetelin, S., Nancy, V., Berger, R., Kaplan, J., Munnich, A., de Gunzburg, J. <strong>cDNA sequence, genomic organization and mapping of PDE6D, the human gene encoding the delta subunit of the cGMP phosphodiesterase of retinal rod cells to chromosome 2q36.</strong> Cytogenet. Cell Genet. 79: 139-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9533031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9533031</a>] [<a href="https://doi.org/10.1159/000134701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9533031">Ershova et al. (1997)</a> reported that the PDE6D gene encodes a 150-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9533031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Li, N., Florio, S. K., Pettenati, M. J., Rao, P. N., Beavo, J. A., Baehr, W. <strong>Characterization of human and mouse rod cGMP phosphodiesterase delta subunit (PDE6D) and chromosomal localization of the human gene.</strong> Genomics 49: 76-82, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570951</a>] [<a href="https://doi.org/10.1006/geno.1998.5210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570951">Li et al. (1998)</a> isolated both mouse and human PDE6D cDNAs from retinal libraries, using a bovine probe. They found that the predicted 150-amino acid polypeptides are unusually well conserved, with only 1 or 2 conservative substitutions in human, bovine, and mouse PDE6D. Amino acid analysis predicted that the putative mammalian protein is soluble and acidic, contains 2 N-linked glycosylation sites, and lacks hydrophobic transmembrane domains. <a href="#6" class="mim-tip-reference" title="Li, N., Florio, S. K., Pettenati, M. J., Rao, P. N., Beavo, J. A., Baehr, W. <strong>Characterization of human and mouse rod cGMP phosphodiesterase delta subunit (PDE6D) and chromosomal localization of the human gene.</strong> Genomics 49: 76-82, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570951</a>] [<a href="https://doi.org/10.1006/geno.1998.5210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570951">Li et al. (1998)</a> found that the mammalian PDE6D genes and the eyeless nematode C. elegans C27H5.1 gene have an identical intron/exon arrangement. The C. elegans C27H5.1 polypeptide shares approximately 70% amino acid similarity with the human PDE6D protein. Southern blot analysis of a variety of species suggested that the sequences of PDE6D are well conserved among vertebrate and invertebrate species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9570951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Northern blot analysis, <a href="#7" class="mim-tip-reference" title="Lorenz, B., Migliaccio, C., Lichtner, P., Meyer, C., Strom, T. M., D'Urso, M., Becker, J., Ciccodicola, A., Meitinger, T. <strong>Cloning and gene structure of the rod cGMP phosphodiesterase delta subunit gene (PDED) in man and mouse.</strong> Europ. J. Hum. Genet. 6: 283-290, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781033</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781033">Lorenz et al. (1998)</a> detected a 1.3-kb PDED transcript in human retina, heart, brain, placenta, liver, and skeletal muscle. A preliminary screen of all 5 exons in 20 unrelated patients with autosomal recessive retinitis pigmentosa revealed no PDED mutation. <a href="#7" class="mim-tip-reference" title="Lorenz, B., Migliaccio, C., Lichtner, P., Meyer, C., Strom, T. M., D'Urso, M., Becker, J., Ciccodicola, A., Meitinger, T. <strong>Cloning and gene structure of the rod cGMP phosphodiesterase delta subunit gene (PDED) in man and mouse.</strong> Europ. J. Hum. Genet. 6: 283-290, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781033</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781033">Lorenz et al. (1998)</a> pointed out that the bovine delta subunit solubilizes the normally membrane-bound PDE and is the only subunit expressed in extraocular tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. <strong>A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.</strong> Hum. Mutat. 35: 137-146, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24166846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24166846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24166846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24166846">Thomas et al. (2014)</a> found ubiquitous expression of the PDE6D gene in human embryonic tissues, with highest expression in the central nervous system, renal tubules, and epithelial cells of the respiratory tract. PDE6D localized to the basal body of primary cilia in human fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24166846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Ershova, G., Derre, J., Chetelin, S., Nancy, V., Berger, R., Kaplan, J., Munnich, A., de Gunzburg, J. <strong>cDNA sequence, genomic organization and mapping of PDE6D, the human gene encoding the delta subunit of the cGMP phosphodiesterase of retinal rod cells to chromosome 2q36.</strong> Cytogenet. Cell Genet. 79: 139-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9533031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9533031</a>] [<a href="https://doi.org/10.1159/000134701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9533031">Ershova et al. (1997)</a> reported that the PDE6D gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9533031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lorenz, B., Migliaccio, C., Lichtner, P., Meyer, C., Strom, T. M., D'Urso, M., Becker, J., Ciccodicola, A., Meitinger, T. <strong>Cloning and gene structure of the rod cGMP phosphodiesterase delta subunit gene (PDED) in man and mouse.</strong> Europ. J. Hum. Genet. 6: 283-290, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781033</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781033">Lorenz et al. (1998)</a> reported that the human PDED gene consists of 5 exons spanning at least 30 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By use of a cDNA fragment of the PDE6D gene, <a href="#2" class="mim-tip-reference" title="Ershova, G., Derre, J., Chetelin, S., Nancy, V., Berger, R., Kaplan, J., Munnich, A., de Gunzburg, J. <strong>cDNA sequence, genomic organization and mapping of PDE6D, the human gene encoding the delta subunit of the cGMP phosphodiesterase of retinal rod cells to chromosome 2q36.</strong> Cytogenet. Cell Genet. 79: 139-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9533031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9533031</a>] [<a href="https://doi.org/10.1159/000134701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9533031">Ershova et al. (1997)</a> mapped the human PDE6D gene to 2q36 by fluorescence in situ hybridization (FISH). By PCR analysis of human-hamster somatic cell hybrids, <a href="#6" class="mim-tip-reference" title="Li, N., Florio, S. K., Pettenati, M. J., Rao, P. N., Beavo, J. A., Baehr, W. <strong>Characterization of human and mouse rod cGMP phosphodiesterase delta subunit (PDE6D) and chromosomal localization of the human gene.</strong> Genomics 49: 76-82, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570951</a>] [<a href="https://doi.org/10.1006/geno.1998.5210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570951">Li et al. (1998)</a> mapped the PDE6D gene to the long arm of chromosome 2; by FISH, they localized the gene to 2q35-q36. Based on these results and known synteny, they predicted that the mouse PDE6D gene resides on chromosome 1. By FISH and radiation hybrid mapping, <a href="#7" class="mim-tip-reference" title="Lorenz, B., Migliaccio, C., Lichtner, P., Meyer, C., Strom, T. M., D'Urso, M., Becker, J., Ciccodicola, A., Meitinger, T. <strong>Cloning and gene structure of the rod cGMP phosphodiesterase delta subunit gene (PDED) in man and mouse.</strong> Europ. J. Hum. Genet. 6: 283-290, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781033</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781033">Lorenz et al. (1998)</a> localized the human PDED gene to 2q37. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9533031+9781033+9570951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>cGMP is the cellular second messenger involved in the transduction of visual signals in retinal rod and cone cells. Constitutively synthesized by guanylate cyclase, its level is tightly controlled by modulating its degradation by a specific phosphodiesterase (cGMP-PDE). The enzyme characterized from bovine retinal rod cells is made of a catalytic core consisting of a membrane-associated alpha-beta dimer. An inhibitory gamma subunit enables transducin to regulate the rate of cGMP degradation according to incoming visual signals. The delta subunit (PDE6D) plays a role in stabilizing the catalytic dimer from membranes (<a href="#3" class="mim-tip-reference" title="Florio, S. K., Prusti, R. K., Beavo, J. A. <strong>Solubilization of membrane-bound rod phosphodiesterase by the rod phosphodiesterase recombinant delta subunit.</strong> J. Biol. Chem. 271: 24036-24047, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8798640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8798640</a>] [<a href="https://doi.org/10.1074/jbc.271.39.24036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8798640">Florio et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8798640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDED, which sustains the spatial organization of KRAS (<a href="/entry/190070">190070</a>) by facilitating its diffusion in the cytoplasm (<a href="#1" class="mim-tip-reference" title="Chandra, A., Grecco, H. E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S. A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A. R., Wittinghofer, A., Bastiaens, P. I. H. <strong>The GDI-like solubilizing factor PDE-delta sustains the spatial organization and signalling of Ras family proteins.</strong> Nature Cell Biol. 14: 148-158, 2012. Note: Erratum: Nature Cell Biol. 14: 329 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22179043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22179043</a>] [<a href="https://doi.org/10.1038/ncb2394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22179043">Chandra et al., 2012</a>; <a href="#10" class="mim-tip-reference" title="Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., Baehr, W. <strong>Photoreceptor cGMP phosphodiesterase delta subunit (PDE-delta) functions as a prenyl-binding protein.</strong> J. Biol. Chem. 279: 407-413, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14561760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14561760</a>] [<a href="https://doi.org/10.1074/jbc.M306559200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14561760">Zhang et al., 2004</a>). <a href="#11" class="mim-tip-reference" title="Zimmerman, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., Waldmann, H. <strong>Small molecule inhibition of the KRAS-PDE-delta interaction impairs oncogenic KRAS signalling.</strong> Nature 497: 638-642, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23698361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23698361</a>] [<a href="https://doi.org/10.1038/nature12205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23698361">Zimmerman et al. (2013)</a> reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14561760+22179043+23698361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By tandem affinity purification, <a href="#4" class="mim-tip-reference" title="Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C., Seo, S. <strong>ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting.</strong> Proc. Nat. Acad. Sci. 109: 19691-19696, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150559[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.1210916109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150559">Humbert et al. (2012)</a> found that epitope-tagged PDE6D interacted with several prenylated proteins and small GTPases in HEK293 cells. Coimmunoprecipitation, mutation, and knockdown experiments with human RPE1 retinal pigment epithelium cells and mouse IMCD3 collecting duct cells revealed that PDE6D was involved in a protein network that targeted the phospholipid phosphatase INPP5E (<a href="/entry/613037">613037</a>) to ciliary membranes. PDE6D interacted with the prenylated, but not the soluble, form of INPP5E. The small GTPase ARL13B (<a href="/entry/608922">608922</a>) bound an adjacent region of INPP5E, and overexpression of ARL13B promoted release of INPP5E from PDE6D. Knockdown of ARL13B or the ciliary protein CEP164 (<a href="/entry/614848">614848</a>) reduced or eliminated ciliogenesis in RPE1 cells, whereas PDE6D knockdown had little effect on ciliogenesis. <a href="#4" class="mim-tip-reference" title="Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C., Seo, S. <strong>ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting.</strong> Proc. Nat. Acad. Sci. 109: 19691-19696, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150559[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.1210916109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150559">Humbert et al. (2012)</a> hypothesized that PDE5D, CEP164, and ARL13B mediate sequential steps in targeting INPP5E to ciliary membranes for cilia formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23150559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., Wittinghofer, A. <strong>Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo.</strong> Nature Chem. Biol. 7: 942-949, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22002721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22002721</a>] [<a href="https://doi.org/10.1038/nchembio.686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22002721">Ismail et al. (2011)</a> stated that PDE-delta binds to farnesylated small G proteins. They presented the 1.7-angstrom structure of human PDE-delta in complex with C-terminally farnesylated human RHEB (<a href="/entry/601293">601293</a>). PDE-delta assumed immunoglobulin-like beta-sandwich folds with a flexible loop and a farnesyl-binding pocket. PDE-delta interacted almost exclusively with the C-terminal farnesyl moiety of RHEB. The interaction did not require guanine nucleotide, which bound RHEB on a surface nearly opposite to the PDE-delta-binding site. <a href="#5" class="mim-tip-reference" title="Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., Wittinghofer, A. <strong>Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo.</strong> Nature Chem. Biol. 7: 942-949, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22002721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22002721</a>] [<a href="https://doi.org/10.1038/nchembio.686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22002721">Ismail et al. (2011)</a> observed that the limited contact of PDE-delta with RHEB provides PDE-delta with relaxed specificity for farnesylated cargo proteins. PDE-delta also interacted with a second small G protein, mouse Arl2 (<a href="/entry/601175">601175</a>). The interaction of PDE-delta with Arl2 was dependent upon GTP and caused a conformational change in PDE-delta that closed its farnesyl-binding pocket. In solution, addition of Arl2-GTP dissociated the PDE-delta-farnesylated RHEB complex. Addition of Arl3 (<a href="/entry/604695">604695</a>)-GTP also caused release of farnesylated RHEB from PDE-delta. In transfected canine kidney cells, fluorescence-labeled RHEB showed endoplasmic reticulum (ER) and Golgi localization. Addition of PDE-delta relocalized RHEB into a cytoplasmic and nuclear distribution, and subsequent addition of Arl2-GTP restored RHEB localization to ER and Golgi membranes. <a href="#5" class="mim-tip-reference" title="Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., Wittinghofer, A. <strong>Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo.</strong> Nature Chem. Biol. 7: 942-949, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22002721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22002721</a>] [<a href="https://doi.org/10.1038/nchembio.686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22002721">Ismail et al. (2011)</a> concluded that PDE-delta functions as a solubilization factor for farnesylated RHEB and that ARL2 and ARL3 act in a GTP-dependent manner as allosteric release factors for farnesylated RHEB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22002721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3 sibs, born of consanguineous parents, with Joubert syndrome-22 (JBTS22; <a href="/entry/615665">615665</a>), <a href="#9" class="mim-tip-reference" title="Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. <strong>A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.</strong> Hum. Mutat. 35: 137-146, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24166846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24166846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24166846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24166846">Thomas et al. (2014)</a> identified a homozygous splice site mutation in the PDE6D gene (<a href="#0001">602676.0001</a>). The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The truncated protein localized to the basal body of primary cilia in patient fibroblasts, and the morphology of primary cilia appeared normal. The mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E, and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E targeting via farnesylation. The mutant PDE6D protein was also unable to bind to ARL2 and ARL3. Screening of the PDE6D gene in 940 patients with variable ciliopathy syndromes did not identify any mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24166846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 male infant, born to consanguineous Lebanese parents, with JBTS22, <a href="#8" class="mim-tip-reference" title="Megarbane, A., Hmaimess, G., Bizzari, S., El-Bazzal, L., Al-Ali, M. T., Stora, S., Delague, V., El-Hayek, S. <strong>A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).</strong> Europ. J. Med. Genet. 62: 103576, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423442</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30423442">Megarbane et al. (2019)</a> identified a homozygous mutation in the PDE6D gene (<a href="#0002">602676.0002</a>). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30423442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. <strong>A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.</strong> Hum. Mutat. 35: 137-146, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24166846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24166846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24166846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24166846">Thomas et al. (2014)</a> found that morpholino knockdown of pde6d in zebrafish embryos resulted in microphthalmia, pericardial edema, distended and blocked renal pronephric openings, proximal tubule cysts, and disorganized retinal cell layers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24166846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3 sibs, born of consanguineous parents, with Joubert syndrome-22 (JBTS22; <a href="/entry/615665">615665</a>), <a href="#9" class="mim-tip-reference" title="Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. <strong>A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.</strong> Hum. Mutat. 35: 137-146, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24166846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24166846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24166846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24166846">Thomas et al. (2014)</a> identified a homozygous G-to-A transition in intron 3 of the PDE6D gene (c.140-1G-A), resulting in the skipping of exon 3 and premature termination. The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The truncated protein localized to the basal body of primary cilia in patient fibroblasts, and the morphology of primary cilia appeared normal. Transcription of the mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E (<a href="/entry/613037">613037</a>), and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E targeting via farnesylation. The mutant PDE6D protein was also unable to bind to ARL2 (<a href="/entry/601175">601175</a>) and ARL3 (<a href="/entry/604695">604695</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24166846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1559307932 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1559307932;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=rs1559307932" 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=rs1559307932" 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=RCV000721961" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000721961" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000721961</a>
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<p>In a male infant, born to consanguineous Lebanese parents, with Joubert syndrome-22 (JBTS22; <a href="/entry/615665">615665</a>), <a href="#8" class="mim-tip-reference" title="Megarbane, A., Hmaimess, G., Bizzari, S., El-Bazzal, L., Al-Ali, M. T., Stora, S., Delague, V., El-Hayek, S. <strong>A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).</strong> Europ. J. Med. Genet. 62: 103576, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423442</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30423442">Megarbane et al. (2019)</a> identified a homozygous 1-bp insertion (c.367_368insG, NM_002601.3) in exon 4 of the PDE6D gene, predicted to result in a frameshift and premature termination (Leu123CysfsTer13). The mutation was predicted to remove the last 16 amino acids of the protein, which are in a conserved region associated with protein localization to the plasma membrane. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. It was not present in the dbSNP, 1000 Genomes Project, and gnomAD databases or in an in-house database of 715 Arab individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30423442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 href="https://doi.org/10.1159/000134701" target="_blank">Full Text</a>]
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Florio, S. K., Prusti, R. K., Beavo, J. A.
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[<a href="https://doi.org/10.1074/jbc.271.39.24036" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150559[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=23150559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1210916109" target="_blank">Full Text</a>]
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Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., Wittinghofer, A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22002721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22002721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22002721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nchembio.686" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570951</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9570951" 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.1998.5210" target="_blank">Full Text</a>]
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Lorenz, B., Migliaccio, C., Lichtner, P., Meyer, C., Strom, T. M., D'Urso, M., Becker, J., Ciccodicola, A., Meitinger, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781033</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200215" target="_blank">Full Text</a>]
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<a id="Megarbane2019" class="mim-anchor"></a>
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Megarbane, A., Hmaimess, G., Bizzari, S., El-Bazzal, L., Al-Ali, M. T., Stora, S., Delague, V., El-Hayek, S.
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<strong>A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).</strong>
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Europ. J. Med. Genet. 62: 103576, 2019. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423442</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30423442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2018.11.010" target="_blank">Full Text</a>]
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Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24166846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24166846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24166846[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=24166846" 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/humu.22470" target="_blank">Full Text</a>]
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Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., Baehr, W.
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<strong>Photoreceptor cGMP phosphodiesterase delta subunit (PDE-delta) functions as a prenyl-binding protein.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14561760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14561760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14561760" 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.M306559200" target="_blank">Full Text</a>]
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<a id="Zimmerman2013" class="mim-anchor"></a>
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Zimmerman, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., Waldmann, H.
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<strong>Small molecule inhibition of the KRAS-PDE-delta interaction impairs oncogenic KRAS signalling.</strong>
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Nature 497: 638-642, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23698361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23698361</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23698361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature12205" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 12/28/2020
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Cassandra L. Kniffin - updated : 2/24/2014<br>Patricia A. Hartz - updated : 11/19/2013<br>Patricia A. Hartz - updated : 10/3/2013<br>Ada Hamosh - updated : 7/8/2013<br>Sheryl A. Jankowski - updated : 8/5/1998
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Victor A. McKusick : 6/2/1998
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/29/2020
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/28/2020<br>carol : 12/28/2020<br>carol : 02/25/2014<br>mcolton : 2/25/2014<br>ckniffin : 2/24/2014<br>mgross : 11/20/2013<br>mgross : 11/20/2013<br>mcolton : 11/20/2013<br>mcolton : 11/19/2013<br>mcolton : 11/19/2013<br>mgross : 10/23/2013<br>tpirozzi : 10/3/2013<br>alopez : 7/8/2013<br>carol : 10/7/1998<br>terry : 10/2/1998<br>carol : 8/5/1998<br>dholmes : 7/2/1998<br>carol : 6/2/1998
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602676
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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PHOSPHODIESTERASE 6D; PDE6D
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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PHOSPHODIESTERASE 6D, cGMP-SPECIFIC, ROD, DELTA<br />
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RETINAL ROD PHOTORECEPTOR cGMP PHOSPHODIESTERASE, DELTA SUBUNIT; PDED<br />
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PDE-DELTA
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PDE6D</em></strong>
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</span>
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</p>
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</div>
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<p>
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<strong>
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<em>
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Cytogenetic location: 2q37.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:231,732,433-231,781,282 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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2q37.1
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</td>
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<td>
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<span class="mim-font">
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Joubert syndrome 22
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</td>
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<td>
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<span class="mim-font">
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615665
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>PDE6D is a phosphodiesterase (EC 3.1.4.17) that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al., 2012). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ershova et al. (1997) reported that the PDE6D gene encodes a 150-amino acid protein. </p><p>Li et al. (1998) isolated both mouse and human PDE6D cDNAs from retinal libraries, using a bovine probe. They found that the predicted 150-amino acid polypeptides are unusually well conserved, with only 1 or 2 conservative substitutions in human, bovine, and mouse PDE6D. Amino acid analysis predicted that the putative mammalian protein is soluble and acidic, contains 2 N-linked glycosylation sites, and lacks hydrophobic transmembrane domains. Li et al. (1998) found that the mammalian PDE6D genes and the eyeless nematode C. elegans C27H5.1 gene have an identical intron/exon arrangement. The C. elegans C27H5.1 polypeptide shares approximately 70% amino acid similarity with the human PDE6D protein. Southern blot analysis of a variety of species suggested that the sequences of PDE6D are well conserved among vertebrate and invertebrate species. </p><p>Using Northern blot analysis, Lorenz et al. (1998) detected a 1.3-kb PDED transcript in human retina, heart, brain, placenta, liver, and skeletal muscle. A preliminary screen of all 5 exons in 20 unrelated patients with autosomal recessive retinitis pigmentosa revealed no PDED mutation. Lorenz et al. (1998) pointed out that the bovine delta subunit solubilizes the normally membrane-bound PDE and is the only subunit expressed in extraocular tissues. </p><p>Thomas et al. (2014) found ubiquitous expression of the PDE6D gene in human embryonic tissues, with highest expression in the central nervous system, renal tubules, and epithelial cells of the respiratory tract. PDE6D localized to the basal body of primary cilia in human fibroblasts. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ershova et al. (1997) reported that the PDE6D gene contains 4 exons. </p><p>Lorenz et al. (1998) reported that the human PDED gene consists of 5 exons spanning at least 30 kb of genomic DNA. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By use of a cDNA fragment of the PDE6D gene, Ershova et al. (1997) mapped the human PDE6D gene to 2q36 by fluorescence in situ hybridization (FISH). By PCR analysis of human-hamster somatic cell hybrids, Li et al. (1998) mapped the PDE6D gene to the long arm of chromosome 2; by FISH, they localized the gene to 2q35-q36. Based on these results and known synteny, they predicted that the mouse PDE6D gene resides on chromosome 1. By FISH and radiation hybrid mapping, Lorenz et al. (1998) localized the human PDED gene to 2q37. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>cGMP is the cellular second messenger involved in the transduction of visual signals in retinal rod and cone cells. Constitutively synthesized by guanylate cyclase, its level is tightly controlled by modulating its degradation by a specific phosphodiesterase (cGMP-PDE). The enzyme characterized from bovine retinal rod cells is made of a catalytic core consisting of a membrane-associated alpha-beta dimer. An inhibitory gamma subunit enables transducin to regulate the rate of cGMP degradation according to incoming visual signals. The delta subunit (PDE6D) plays a role in stabilizing the catalytic dimer from membranes (Florio et al., 1996). </p><p>Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDED, which sustains the spatial organization of KRAS (190070) by facilitating its diffusion in the cytoplasm (Chandra et al., 2012; Zhang et al., 2004). Zimmerman et al. (2013) reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. </p><p>By tandem affinity purification, Humbert et al. (2012) found that epitope-tagged PDE6D interacted with several prenylated proteins and small GTPases in HEK293 cells. Coimmunoprecipitation, mutation, and knockdown experiments with human RPE1 retinal pigment epithelium cells and mouse IMCD3 collecting duct cells revealed that PDE6D was involved in a protein network that targeted the phospholipid phosphatase INPP5E (613037) to ciliary membranes. PDE6D interacted with the prenylated, but not the soluble, form of INPP5E. The small GTPase ARL13B (608922) bound an adjacent region of INPP5E, and overexpression of ARL13B promoted release of INPP5E from PDE6D. Knockdown of ARL13B or the ciliary protein CEP164 (614848) reduced or eliminated ciliogenesis in RPE1 cells, whereas PDE6D knockdown had little effect on ciliogenesis. Humbert et al. (2012) hypothesized that PDE5D, CEP164, and ARL13B mediate sequential steps in targeting INPP5E to ciliary membranes for cilia formation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ismail et al. (2011) stated that PDE-delta binds to farnesylated small G proteins. They presented the 1.7-angstrom structure of human PDE-delta in complex with C-terminally farnesylated human RHEB (601293). PDE-delta assumed immunoglobulin-like beta-sandwich folds with a flexible loop and a farnesyl-binding pocket. PDE-delta interacted almost exclusively with the C-terminal farnesyl moiety of RHEB. The interaction did not require guanine nucleotide, which bound RHEB on a surface nearly opposite to the PDE-delta-binding site. Ismail et al. (2011) observed that the limited contact of PDE-delta with RHEB provides PDE-delta with relaxed specificity for farnesylated cargo proteins. PDE-delta also interacted with a second small G protein, mouse Arl2 (601175). The interaction of PDE-delta with Arl2 was dependent upon GTP and caused a conformational change in PDE-delta that closed its farnesyl-binding pocket. In solution, addition of Arl2-GTP dissociated the PDE-delta-farnesylated RHEB complex. Addition of Arl3 (604695)-GTP also caused release of farnesylated RHEB from PDE-delta. In transfected canine kidney cells, fluorescence-labeled RHEB showed endoplasmic reticulum (ER) and Golgi localization. Addition of PDE-delta relocalized RHEB into a cytoplasmic and nuclear distribution, and subsequent addition of Arl2-GTP restored RHEB localization to ER and Golgi membranes. Ismail et al. (2011) concluded that PDE-delta functions as a solubilization factor for farnesylated RHEB and that ARL2 and ARL3 act in a GTP-dependent manner as allosteric release factors for farnesylated RHEB. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 3 sibs, born of consanguineous parents, with Joubert syndrome-22 (JBTS22; 615665), Thomas et al. (2014) identified a homozygous splice site mutation in the PDE6D gene (602676.0001). The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The truncated protein localized to the basal body of primary cilia in patient fibroblasts, and the morphology of primary cilia appeared normal. The mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E, and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E targeting via farnesylation. The mutant PDE6D protein was also unable to bind to ARL2 and ARL3. Screening of the PDE6D gene in 940 patients with variable ciliopathy syndromes did not identify any mutations. </p><p>In a male infant, born to consanguineous Lebanese parents, with JBTS22, Megarbane et al. (2019) identified a homozygous mutation in the PDE6D gene (602676.0002). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Thomas et al. (2014) found that morpholino knockdown of pde6d in zebrafish embryos resulted in microphthalmia, pericardial edema, distended and blocked renal pronephric openings, proximal tubule cysts, and disorganized retinal cell layers. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>2 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 JOUBERT SYNDROME 22</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PDE6D, IVS3AS, G-A, -1
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<br />
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SNP: rs587777156,
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ClinVar: RCV000087137
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 sibs, born of consanguineous parents, with Joubert syndrome-22 (JBTS22; 615665), Thomas et al. (2014) identified a homozygous G-to-A transition in intron 3 of the PDE6D gene (c.140-1G-A), resulting in the skipping of exon 3 and premature termination. The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The truncated protein localized to the basal body of primary cilia in patient fibroblasts, and the morphology of primary cilia appeared normal. Transcription of the mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E (613037), and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E targeting via farnesylation. The mutant PDE6D protein was also unable to bind to ARL2 (601175) and ARL3 (604695). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 JOUBERT SYNDROME 22</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PDE6D, 1-BP INS, 367G
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<br />
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SNP: rs1559307932,
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ClinVar: RCV000721961
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male infant, born to consanguineous Lebanese parents, with Joubert syndrome-22 (JBTS22; 615665), Megarbane et al. (2019) identified a homozygous 1-bp insertion (c.367_368insG, NM_002601.3) in exon 4 of the PDE6D gene, predicted to result in a frameshift and premature termination (Leu123CysfsTer13). The mutation was predicted to remove the last 16 amino acids of the protein, which are in a conserved region associated with protein localization to the plasma membrane. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. It was not present in the dbSNP, 1000 Genomes Project, and gnomAD databases or in an in-house database of 715 Arab individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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