3581 lines
260 KiB
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3581 lines
260 KiB
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Entry
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- *604212 - POLYADENYLATE-SPECIFIC RIBONUCLEASE; PARN
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- OMIM
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<p>
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<span class="h4">*604212</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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/604212">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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<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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<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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<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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<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=ENSG00000140694;t=ENST00000437198" 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=5073" 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=604212" 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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<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=ENSG00000140694;t=ENST00000437198" 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_001134477,NM_001242992,NM_002582,XM_011522514,XM_047434181,XM_047434182,XM_047434183,XM_047434184,XM_047434185,XR_007064881,XR_007064882,XR_007064883,XR_007064884" 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_002582" 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=604212" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=07250&isoform_id=07250_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/PARN" 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/3776076,4505611,29477165,60390262,119605516,119605517,189054660,193785796,194375568,194377130,194382480,194389110,197333695,339715201,767987272,2217306145,2217306147,2217306152,2217306154,2217306158,2462490637,2462490639,2462490644,2462490646,2462490649,2462490651,2462549186,2462549188,2462549190,2462549192,2462549194,2462549196,2462549198,2462549200,2462549202,2462549204,2462549206" 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/O95453" 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=5073" 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=ENSG00000140694;t=ENST00000437198" 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=PARN" 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=PARN" 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+5073" 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/PARN" 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:5073" 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/5073" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000437198.7&hgg_start=14435701&hgg_end=14630260&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://search.clinicalgenome.org/kb/genes/HGNC:8609" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604212[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=604212[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/PARN/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000140694" 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=PARN" 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=PARN" 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=PARN" 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=PARN&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/PA32949" 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:8609" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1921358" 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/PARN#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:1921358" 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/5073/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=5073" 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=WBGene00010734;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-040426-880" 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:5073" 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=PARN&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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604212
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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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POLYADENYLATE-SPECIFIC RIBONUCLEASE; PARN
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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">
|
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POLY(A)-SPECIFIC RIBONUCLEASE<br />
|
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DEADENYLATING NUCLEASE; DAN
|
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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=PARN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PARN</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/16/209?start=-3&limit=10&highlight=209">16p13.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:14435701-14630260&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:14,435,701-14,630,260</a> </span>
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616353,616371" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
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</span>
|
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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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>
|
|
|
|
<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/16/209?start=-3&limit=10&highlight=209">
|
|
16p13.12
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Dyskeratosis congenita, autosomal recessive 6
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616353"> 616353 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<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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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616371"> 616371 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<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>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604212" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/604212" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<p>The PARN gene, which belongs to a highly conserved family of exoribonucleases, acts by shortening mRNA poly(A) tail length through the process of deadenylation, thus regulating gene expression (summary by <a href="#6" class="mim-tip-reference" title="Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. <strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong> J. Clin. Invest. 125: 2151-2160, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI78963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25893599">Tummala et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25893599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. <a href="#2" class="mim-tip-reference" title="Korner, C. G., Wahle, E. <strong>Poly(A) tail shortening by a mammalian poly(A)-specific 3-prime-exoribonuclease.</strong> J. Biol. Chem. 272: 10448-10456, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9099687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9099687</a>] [<a href="https://doi.org/10.1074/jbc.272.16.10448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9099687">Korner and Wahle (1997)</a> purified the enzyme for deadenylation, PARN, which they named DAN, from calf thymus. <a href="#3" class="mim-tip-reference" title="Korner, C. G., Wormington, M., Muckenthaler, M., Schneider, S., Dehlin, E., Wahle, E. <strong>The deadenylating nuclease (DAN) is involved in poly(A) tail removal during the meiotic maturation of Xenopus oocytes.</strong> EMBO J. 17: 5427-5437, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9736620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9736620</a>] [<a href="https://doi.org/10.1093/emboj/17.18.5427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9736620">Korner et al. (1998)</a> partially sequenced the bovine PARN protein. By searching an EST database with the bovine PARN peptide sequences, they identified a human PARN EST encoding a deduced 639-amino acid protein. The calculated molecular mass of human PARN is 73.5 kD, which was the mass of recombinant PARN expressed in E. coli. The human PARN protein shows sequence similarity to the RNase D family of 3-prime exonucleases, which includes E. coli polymerase I. PARN is a 3-prime exonuclease that prefers poly(A) as the substrate. In an in vitro assay, PARN activity was partially inhibited by PAB1 (<a href="/entry/604679">604679</a>), resulting in phased shortening of the poly(A) tail of the polyadenylated RNA substrate. The PARN protein is located in both the nucleus and the cytoplasm. It is not stably associated with polysomes or ribosomal subunits. Northern blot analysis detected a 3.1-kb PARN transcript in HeLa cell extracts. The authors noted that the PARN gene is widely expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9736620+9099687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Korner, C. G., Wormington, M., Muckenthaler, M., Schneider, S., Dehlin, E., Wahle, E. <strong>The deadenylating nuclease (DAN) is involved in poly(A) tail removal during the meiotic maturation of Xenopus oocytes.</strong> EMBO J. 17: 5427-5437, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9736620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9736620</a>] [<a href="https://doi.org/10.1093/emboj/17.18.5427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9736620">Korner et al. (1998)</a> noted that the PARN gene maps to chromosome 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9736620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. <strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong> J. Med. Genet. 52: 738-748, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26342108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26342108</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26342108">Dhanraj et al. (2015)</a> demonstrated that knockdown of PARN in human bone marrow CD34+ progenitor cells resulted in smaller colonies and a marked reduction in hematopoietic colony formation compared to controls. Morpholino knockdown of the parn gene in zebrafish resulted in anemia and leukopenia, which was rescued by human PARN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26342108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 somatic cells and induced pluripotent stem cells (iPSCs) from patients with dyskeratosis congenita with PARN mutations (DKCB6; <a href="/entry/616353">616353</a>), <a href="#4" class="mim-tip-reference" title="Moon, D. H., Segal, M., Boyraz, B., Guinan, E., Hofmann, I., Cahan, P., Tai, A. K., Agarwal, S. <strong>Poly(A)-specific ribonuclease (PARN) mediates 3-prime-end maturation of the telomerase RNA component.</strong> Nature Genet. 47: 1482-1488, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26482878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26482878</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26482878[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26482878">Moon et al. (2015)</a> demonstrated that PARN is required for the 3-prime-end maturation of the telomerase RNA component (TERC; <a href="/entry/602322">602322</a>). Patient-derived cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3-prime termini showed that PARN is required for removal of posttranscriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased proportion of oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. <a href="#4" class="mim-tip-reference" title="Moon, D. H., Segal, M., Boyraz, B., Guinan, E., Hofmann, I., Cahan, P., Tai, A. K., Agarwal, S. <strong>Poly(A)-specific ribonuclease (PARN) mediates 3-prime-end maturation of the telomerase RNA component.</strong> Nature Genet. 47: 1482-1488, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26482878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26482878</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26482878[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26482878">Moon et al. (2015)</a> concluded that their results showed a novel role for PARN in the biogenesis of TERC and provided a mechanism linking PARN mutations to telomere diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26482878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Autosomal Recessive Dyskeratosis Congenita 6</em></strong></p><p>
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In 4 children from 3 unrelated families with autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>) associated with shortened telomeres, <a href="#6" class="mim-tip-reference" title="Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. <strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong> J. Clin. Invest. 125: 2151-2160, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI78963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25893599">Tummala et al. (2015)</a> identified homozygous or compound heterozygous mutations in the PARN gene (<a href="#0001">604212.0001</a>-<a href="#0004">604212.0004</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Studies of 1 patient's cells (A383V; <a href="#0001">604212.0001</a>) showed reduced deadenylation activity, early DNA damage response with abnormal nuclear p53 (TP53; <a href="/entry/191170">191170</a>) expression, cell cycle arrest, and reduced cell viability upon UV treatment. Patient cells showed decreased expression of genes involved in telomere maintenance. The findings suggested a role for PARN in telomere maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25893599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 21-year-old woman with a severe form of DKCB6 and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome, <a href="#1" class="mim-tip-reference" title="Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. <strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong> J. Med. Genet. 52: 738-748, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26342108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26342108</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26342108">Dhanraj et al. (2015)</a> identified compound heterozygous mutations in the PARN gene (<a href="#0009">604212.0009</a> and <a href="#0010">604212.0010</a>). Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (<a href="/entry/602322">602322</a>), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects. One of the mutant alleles carried an intragenic deletion that was inherited from the mother who had an unspecified mental illness requiring admission to a psychiatric ward. <a href="#1" class="mim-tip-reference" title="Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. <strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong> J. Med. Genet. 52: 738-748, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26342108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26342108</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26342108">Dhanraj et al. (2015)</a> also reported 2 unrelated children, aged 9 and 10 years, who had de novo monoallelic intragenic PARN deletions associated with global developmental delay and mild dysmorphic features, but no evidence of bone marrow failure. The findings indicated that loss of the PARN gene may be associated with neurologic deficits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26342108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome 4</em></strong></p><p>
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In affected members of 6 unrelated families with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; <a href="/entry/616371">616371</a>), <a href="#5" class="mim-tip-reference" title="Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. <strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong> Nature Genet. 47: 512-517, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25848748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25848748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25848748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25848748">Stuart et al. (2015)</a> identified 6 different heterozygous mutations in the PARN gene (see, e.g., <a href="#0005">604212.0005</a>-<a href="#0008">604212.0008</a>). Five of the mutations were truncating, consistent with haploinsufficiency; 1 was a missense mutation. The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 9 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. There was also evidence of environmental influences, e.g., smoking and occupational factors. Cells from patients with truncating mutations showed reduced protein expression, but additional functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25848748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604212[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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PARN, ALA383VAL (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000206797" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000206797</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786200999 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200999;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=rs786200999" 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=rs786200999" 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=RCV000162313 OR RCV000170484" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162313, RCV000170484" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162313...</a>
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<p>In 2 sibs, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>), <a href="#6" class="mim-tip-reference" title="Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. <strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong> J. Clin. Invest. 125: 2151-2160, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI78963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25893599">Tummala et al. (2015)</a> identified a homozygous c.1148C-T transition (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000206797" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000206797</a>) in the PARN gene, resulting in an ala383-to-val (A383V) substitution at a highly conserved residue affecting an alpha helix in nuclease domain-2 (ND2). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. Patient lymphoid cells showed that the mutant A383V PARN protein had normal subcellular localization and levels of expression, but had decreased basal deadenylation activity as well as decreased activity after UV exposure and DNA damage compared to wildtype. Patient cells also showed increased cell death after UV exposure, and viable cells were arrested in the G2/M phase, indicating abnormal cell cycle regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25893599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0002 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
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PARN, IVS13DS, G-T, +1 (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000206798" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000206798</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs756132866 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs756132866;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs756132866?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs756132866" 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=rs756132866" 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=RCV000162314 OR RCV000170485" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162314, RCV000170485" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162314...</a>
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<p>In a boy, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>), <a href="#6" class="mim-tip-reference" title="Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. <strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong> J. Clin. Invest. 125: 2151-2160, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI78963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25893599">Tummala et al. (2015)</a> identified a homozygous G-to-T transversion (c.918+1G-T; <a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000206798" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000206798</a>) in intron 13 of the PARN gene. The mutation resulted in the generation of 2 abnormal transcripts: the skipping of exon 13 causing an in-frame deletion of residues 281-306 (281_306del) in nuclease domain-2 (ND2), and the skipping of exons 13 and 14 resulting in a frameshift and premature termination (Gly281ThrfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25893599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
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PARN, 1-BP DUP, 863A (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000206799" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000206799</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786201001 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786201001;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=rs786201001" 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=rs786201001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000162315 OR RCV000170486" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162315, RCV000170486" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162315...</a>
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<p>In a boy with autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>), <a href="#6" class="mim-tip-reference" title="Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. <strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong> J. Clin. Invest. 125: 2151-2160, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI78963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25893599">Tummala et al. (2015)</a> identified compound heterozygous mutations in the PARN gene: a 1-bp duplication (c.863dupA; <a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000206799" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000206799</a>), resulting in a frameshift and premature termination (Asn288LysfsTer23), and a 4-bp deletion (c.659+4_659+7delAGTA; <a href="#0004">604212.0004</a>) in intron 9, predicted to result in abnormal splicing, the skipping of exon 9, and an in-frame deletion (208_220del) in the R3H domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25893599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
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PARN, 4-BP DEL, 659AGTA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs759131762 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759131762;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs759131762?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs759131762" 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=rs759131762" 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=RCV000162315 OR RCV000170487 OR RCV002516543 OR RCV003327376" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162315, RCV000170487, RCV002516543, RCV003327376" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162315...</a>
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<p>For discussion of the 4-bp deletion in intron 9 of the PARN gene that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>) by <a href="#6" class="mim-tip-reference" title="Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. <strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong> J. Clin. Invest. 125: 2151-2160, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI78963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25893599">Tummala et al. (2015)</a>, see <a href="#0003">604212.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25893599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs751381953 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs751381953;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs751381953?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs751381953" 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=rs751381953" 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=RCV000170589 OR RCV002509272" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170589, RCV002509272" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170589...</a>
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<p>In 2 affected members of a large kindred (F349/F373) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; <a href="/entry/616371">616371</a>), <a href="#5" class="mim-tip-reference" title="Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. <strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong> Nature Genet. 47: 512-517, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25848748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25848748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25848748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25848748">Stuart et al. (2015)</a> identified a heterozygous A-to-G transition (c.246-2A-G, NM_002582.3) in intron 4 of the PARN gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. Telomere length in the 2 patients was less than 1% of control length. DNA was not available from 3 other affected family members or from 2 family members with an unspecified lung disease, but the presence of the mutation in these individuals was inferred on the basis of location in the pedigree. There were at least 6 unaffected mutation carriers, consistent with incomplete penetrance. Environmental influences such as smoking and occupational factors were also present in those affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25848748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
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PARN, GLN177TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs876661305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs876661305;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=rs876661305" 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=rs876661305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000170590 OR RCV001311427 OR RCV002509273 OR RCV003765062" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170590, RCV001311427, RCV002509273, RCV003765062" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170590...</a>
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<span class="mim-text-font">
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<p>In 2 affected members of a family (F70) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; <a href="/entry/616371">616371</a>) and 1 member with an unspecified lung disease, <a href="#5" class="mim-tip-reference" title="Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. <strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong> Nature Genet. 47: 512-517, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25848748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25848748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25848748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25848748">Stuart et al. (2015)</a> identified a heterozygous c.529C-T transition (c.529C-T, NM_002582.3) in the PARN gene, resulting in a gln177-to-ter (Q177X) substitution in the CAF1 ribonuclease domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from 2 other family members with PFBMFT4 or from 1 other member with an unspecified lung disease, but the presence of the mutation in these individuals was inferred on the basis of location in the pedigree. Telomere length in the proband was less than 1% of control length. There were at least 6 unaffected mutation carriers, consistent with incomplete penetrance. Environmental influences such as smoking and occupational factors were also present in those affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25848748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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PARN, 1-BP INS, 563T
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs878853260 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853260;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs878853260?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs878853260" 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=rs878853260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000170591 OR RCV000701508 OR RCV002509274" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170591, RCV000701508, RCV002509274" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170591...</a>
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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 2 sibs (F416) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; <a href="/entry/616371">616371</a>), <a href="#5" class="mim-tip-reference" title="Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. <strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong> Nature Genet. 47: 512-517, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25848748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25848748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25848748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25848748">Stuart et al. (2015)</a> identified a heterozygous 1-bp insertion (c.563_564insT, NM_002582.3) in the PARN gene, resulting in a frameshift and premature termination (Ile188IlefsTer7) in the CAF1 ribonuclease domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from 4 other affected family members. Telomere length in the proband was about 7% of control length. Two affected family members also had premature graying. Environmental influences such as smoking and occupational factors were present in those affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25848748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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PARN, LYS421ARG
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs777090017 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777090017;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs777090017?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs777090017" 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=rs777090017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000170592 OR RCV003765063" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170592, RCV003765063" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170592...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (F432) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; <a href="/entry/616371">616371</a>), <a href="#5" class="mim-tip-reference" title="Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. <strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong> Nature Genet. 47: 512-517, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25848748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25848748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25848748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25848748">Stuart et al. (2015)</a> identified a heterozygous c.1262A-G transition (c.1262A-G, NM_002582.3) in the PARN gene, resulting in a lys421-to-arg (K421R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from an affected cousin of the proband or from 3 other family members with an unspecified lung disease. Telomere length in the proband was less than 1% of control length. Environmental influences such as smoking and occupational factors were present in those affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25848748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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</span>
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<div>
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</div>
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<div>
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<div>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</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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<div style="float: left;">
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PARN, ARG349TRP
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs754368658 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs754368658;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs754368658?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs754368658" 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=rs754368658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000203540 OR RCV002517366 OR RCV003325405" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203540, RCV002517366, RCV003325405" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203540...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 21-year-old woman with a severe form of autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>) and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome, <a href="#1" class="mim-tip-reference" title="Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. <strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong> J. Med. Genet. 52: 738-748, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26342108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26342108</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26342108">Dhanraj et al. (2015)</a> identified compound heterozygous mutations in the PARN gene: a c.1045C-T transition in exon 16, resulting in an arg349-to-trp (R349W) substitution in the nuclease domain, and a 22-kb intragenic deletion (<a href="#0010">604212.0010</a>) including exons 14 to 18 and resulting in a frameshift and premature termination (Asp307ValfsTer22): Sanger sequencing of the cDNA revealed c.919-1262del344. The truncated protein was predicted to lack essential catalytic parts of the nuclease domain and the RNA recognition motif. The R349W mutation was inherited from the unaffected father, whereas the intragenic deletion was inherited from the mother who had an unspecified mental illness requiring admission to a psychiatric ward. The R349W mutation was not found in over 2,000 control individuals, but it was reported at a low frequency (8.32 x 10(-6)) in the ExAC database. Patient cells showed significantly decreased PARN mRNA levels, suggesting that the deletion resulted in nonsense-mediated mRNA decay. PARN protein levels were also decreased. In vitro functional expression studies showed that the R349W mutant protein had markedly reduced deadenylation activity (about 50%) compared to wildtype. Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (<a href="/entry/602322">602322</a>), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26342108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
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PARN, 22-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000203556" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203556" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203556</a>
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<p>For discussion of the 22-kb deletion (c.919_1262del344) in the PARN gene that was found in compound heterozygous state in a patient with a severe form of autosomal recessive dyskeratosis congenita-6 (DKCB6; <a href="/entry/616353">616353</a>) and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome by <a href="#1" class="mim-tip-reference" title="Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. <strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong> J. Med. Genet. 52: 738-748, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26342108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26342108</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26342108">Dhanraj et al. (2015)</a>, see <a href="#0009">604212.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26342108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others.
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<strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong>
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J. Med. Genet. 52: 738-748, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26342108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26342108</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26342108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2015-103292" target="_blank">Full Text</a>]
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Korner, C. G., Wahle, E.
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<strong>Poly(A) tail shortening by a mammalian poly(A)-specific 3-prime-exoribonuclease.</strong>
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J. Biol. Chem. 272: 10448-10456, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9099687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9099687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9099687" 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.272.16.10448" target="_blank">Full Text</a>]
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Korner, C. G., Wormington, M., Muckenthaler, M., Schneider, S., Dehlin, E., Wahle, E.
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<strong>The deadenylating nuclease (DAN) is involved in poly(A) tail removal during the meiotic maturation of Xenopus oocytes.</strong>
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EMBO J. 17: 5427-5437, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9736620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9736620</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9736620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/emboj/17.18.5427" target="_blank">Full Text</a>]
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<a id="Moon2015" class="mim-anchor"></a>
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Moon, D. H., Segal, M., Boyraz, B., Guinan, E., Hofmann, I., Cahan, P., Tai, A. K., Agarwal, S.
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<strong>Poly(A)-specific ribonuclease (PARN) mediates 3-prime-end maturation of the telomerase RNA component.</strong>
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Nature Genet. 47: 1482-1488, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26482878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26482878</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26482878[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=26482878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.3423" target="_blank">Full Text</a>]
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Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others.
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<strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong>
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Nature Genet. 47: 512-517, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25848748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25848748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25848748[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=25848748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.3278" target="_blank">Full Text</a>]
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Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I.
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<strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong>
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J. Clin. Invest. 125: 2151-2160, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25893599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25893599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25893599[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=25893599" 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/10.1172/JCI78963" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 02/08/2016
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Cassandra L. Kniffin - updated : 1/7/2016<br>Cassandra L. Kniffin - updated : 5/18/2015<br>Cassandra L. Kniffin - updated : 5/11/2015<br>Patti M. Sherman - updated : 10/5/1999
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alopez : 05/08/2023<br>alopez : 05/08/2023<br>alopez : 02/08/2016<br>carol : 1/12/2016<br>ckniffin : 1/7/2016<br>alopez : 9/18/2015<br>carol : 5/20/2015<br>mcolton : 5/18/2015<br>ckniffin : 5/18/2015<br>carol : 5/13/2015<br>carol : 5/12/2015<br>mcolton : 5/11/2015<br>ckniffin : 5/11/2015<br>carol : 3/21/2014<br>mgross : 3/14/2000<br>mgross : 10/5/1999<br>psherman : 10/5/1999<br>psherman : 10/1/1999
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POLY(A)-SPECIFIC RIBONUCLEASE<br />
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Cytogenetic location: 16p13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:14,435,701-14,630,260 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
16p13.12
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Dyskeratosis congenita, autosomal recessive 6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616353
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616371
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The PARN gene, which belongs to a highly conserved family of exoribonucleases, acts by shortening mRNA poly(A) tail length through the process of deadenylation, thus regulating gene expression (summary by Tummala et al., 2015). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. Korner and Wahle (1997) purified the enzyme for deadenylation, PARN, which they named DAN, from calf thymus. Korner et al. (1998) partially sequenced the bovine PARN protein. By searching an EST database with the bovine PARN peptide sequences, they identified a human PARN EST encoding a deduced 639-amino acid protein. The calculated molecular mass of human PARN is 73.5 kD, which was the mass of recombinant PARN expressed in E. coli. The human PARN protein shows sequence similarity to the RNase D family of 3-prime exonucleases, which includes E. coli polymerase I. PARN is a 3-prime exonuclease that prefers poly(A) as the substrate. In an in vitro assay, PARN activity was partially inhibited by PAB1 (604679), resulting in phased shortening of the poly(A) tail of the polyadenylated RNA substrate. The PARN protein is located in both the nucleus and the cytoplasm. It is not stably associated with polysomes or ribosomal subunits. Northern blot analysis detected a 3.1-kb PARN transcript in HeLa cell extracts. The authors noted that the PARN gene is widely expressed. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Korner et al. (1998) noted that the PARN gene maps to chromosome 16. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Dhanraj et al. (2015) demonstrated that knockdown of PARN in human bone marrow CD34+ progenitor cells resulted in smaller colonies and a marked reduction in hematopoietic colony formation compared to controls. Morpholino knockdown of the parn gene in zebrafish resulted in anemia and leukopenia, which was rescued by human PARN. </p><p>Using somatic cells and induced pluripotent stem cells (iPSCs) from patients with dyskeratosis congenita with PARN mutations (DKCB6; 616353), Moon et al. (2015) demonstrated that PARN is required for the 3-prime-end maturation of the telomerase RNA component (TERC; 602322). Patient-derived cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3-prime termini showed that PARN is required for removal of posttranscriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased proportion of oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Moon et al. (2015) concluded that their results showed a novel role for PARN in the biogenesis of TERC and provided a mechanism linking PARN mutations to telomere diseases. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Autosomal Recessive Dyskeratosis Congenita 6</em></strong></p><p>
|
|
In 4 children from 3 unrelated families with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) associated with shortened telomeres, Tummala et al. (2015) identified homozygous or compound heterozygous mutations in the PARN gene (604212.0001-604212.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Studies of 1 patient's cells (A383V; 604212.0001) showed reduced deadenylation activity, early DNA damage response with abnormal nuclear p53 (TP53; 191170) expression, cell cycle arrest, and reduced cell viability upon UV treatment. Patient cells showed decreased expression of genes involved in telomere maintenance. The findings suggested a role for PARN in telomere maintenance. </p><p>In a 21-year-old woman with a severe form of DKCB6 and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome, Dhanraj et al. (2015) identified compound heterozygous mutations in the PARN gene (604212.0009 and 604212.0010). Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (602322), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects. One of the mutant alleles carried an intragenic deletion that was inherited from the mother who had an unspecified mental illness requiring admission to a psychiatric ward. Dhanraj et al. (2015) also reported 2 unrelated children, aged 9 and 10 years, who had de novo monoallelic intragenic PARN deletions associated with global developmental delay and mild dysmorphic features, but no evidence of bone marrow failure. The findings indicated that loss of the PARN gene may be associated with neurologic deficits. </p><p><strong><em>Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome 4</em></strong></p><p>
|
|
In affected members of 6 unrelated families with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified 6 different heterozygous mutations in the PARN gene (see, e.g., 604212.0005-604212.0008). Five of the mutations were truncating, consistent with haploinsufficiency; 1 was a missense mutation. The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 9 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. There was also evidence of environmental influences, e.g., smoking and occupational factors. Cells from patients with truncating mutations showed reduced protein expression, but additional functional studies were not performed. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>10 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PARN, ALA383VAL ({dbSNP SCV000206797})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786200999,
|
|
|
|
|
|
|
|
ClinVar: RCV000162313, RCV000170484
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353), Tummala et al. (2015) identified a homozygous c.1148C-T transition (SCV000206797) in the PARN gene, resulting in an ala383-to-val (A383V) substitution at a highly conserved residue affecting an alpha helix in nuclease domain-2 (ND2). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. Patient lymphoid cells showed that the mutant A383V PARN protein had normal subcellular localization and levels of expression, but had decreased basal deadenylation activity as well as decreased activity after UV exposure and DNA damage compared to wildtype. Patient cells also showed increased cell death after UV exposure, and viable cells were arrested in the G2/M phase, indicating abnormal cell cycle regulation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PARN, IVS13DS, G-T, +1 ({dbSNP SCV000206798})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs756132866,
|
|
|
|
|
|
gnomAD: rs756132866,
|
|
|
|
|
|
ClinVar: RCV000162314, RCV000170485
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353), Tummala et al. (2015) identified a homozygous G-to-T transversion (c.918+1G-T; SCV000206798) in intron 13 of the PARN gene. The mutation resulted in the generation of 2 abnormal transcripts: the skipping of exon 13 causing an in-frame deletion of residues 281-306 (281_306del) in nuclease domain-2 (ND2), and the skipping of exons 13 and 14 resulting in a frameshift and premature termination (Gly281ThrfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PARN, 1-BP DUP, 863A ({dbSNP SCV000206799})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786201001,
|
|
|
|
|
|
|
|
ClinVar: RCV000162315, RCV000170486
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353), Tummala et al. (2015) identified compound heterozygous mutations in the PARN gene: a 1-bp duplication (c.863dupA; SCV000206799), resulting in a frameshift and premature termination (Asn288LysfsTer23), and a 4-bp deletion (c.659+4_659+7delAGTA; 604212.0004) in intron 9, predicted to result in abnormal splicing, the skipping of exon 9, and an in-frame deletion (208_220del) in the R3H domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PARN, 4-BP DEL, 659AGTA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs759131762,
|
|
|
|
|
|
gnomAD: rs759131762,
|
|
|
|
|
|
ClinVar: RCV000162315, RCV000170487, RCV002516543, RCV003327376
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 4-bp deletion in intron 9 of the PARN gene that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) by Tummala et al. (2015), see 604212.0003. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PARN, IVS4AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs751381953,
|
|
|
|
|
|
gnomAD: rs751381953,
|
|
|
|
|
|
ClinVar: RCV000170589, RCV002509272
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a large kindred (F349/F373) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified a heterozygous A-to-G transition (c.246-2A-G, NM_002582.3) in intron 4 of the PARN gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. Telomere length in the 2 patients was less than 1% of control length. DNA was not available from 3 other affected family members or from 2 family members with an unspecified lung disease, but the presence of the mutation in these individuals was inferred on the basis of location in the pedigree. There were at least 6 unaffected mutation carriers, consistent with incomplete penetrance. Environmental influences such as smoking and occupational factors were also present in those affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PARN, GLN177TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs876661305,
|
|
|
|
|
|
|
|
ClinVar: RCV000170590, RCV001311427, RCV002509273, RCV003765062
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family (F70) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371) and 1 member with an unspecified lung disease, Stuart et al. (2015) identified a heterozygous c.529C-T transition (c.529C-T, NM_002582.3) in the PARN gene, resulting in a gln177-to-ter (Q177X) substitution in the CAF1 ribonuclease domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from 2 other family members with PFBMFT4 or from 1 other member with an unspecified lung disease, but the presence of the mutation in these individuals was inferred on the basis of location in the pedigree. Telomere length in the proband was less than 1% of control length. There were at least 6 unaffected mutation carriers, consistent with incomplete penetrance. Environmental influences such as smoking and occupational factors were also present in those affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PARN, 1-BP INS, 563T
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<br />
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SNP: rs878853260,
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gnomAD: rs878853260,
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ClinVar: RCV000170591, RCV000701508, RCV002509274
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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 2 sibs (F416) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified a heterozygous 1-bp insertion (c.563_564insT, NM_002582.3) in the PARN gene, resulting in a frameshift and premature termination (Ile188IlefsTer7) in the CAF1 ribonuclease domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from 4 other affected family members. Telomere length in the proband was about 7% of control length. Two affected family members also had premature graying. Environmental influences such as smoking and occupational factors were present in those affected. </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>.0008 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PARN, LYS421ARG
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<br />
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SNP: rs777090017,
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gnomAD: rs777090017,
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ClinVar: RCV000170592, RCV003765063
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (F432) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified a heterozygous c.1262A-G transition (c.1262A-G, NM_002582.3) in the PARN gene, resulting in a lys421-to-arg (K421R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from an affected cousin of the proband or from 3 other family members with an unspecified lung disease. Telomere length in the proband was less than 1% of control length. Environmental influences such as smoking and occupational factors were present in those affected. </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>.0009 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</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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PARN, ARG349TRP
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<br />
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SNP: rs754368658,
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gnomAD: rs754368658,
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ClinVar: RCV000203540, RCV002517366, RCV003325405
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 21-year-old woman with a severe form of autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome, Dhanraj et al. (2015) identified compound heterozygous mutations in the PARN gene: a c.1045C-T transition in exon 16, resulting in an arg349-to-trp (R349W) substitution in the nuclease domain, and a 22-kb intragenic deletion (604212.0010) including exons 14 to 18 and resulting in a frameshift and premature termination (Asp307ValfsTer22): Sanger sequencing of the cDNA revealed c.919-1262del344. The truncated protein was predicted to lack essential catalytic parts of the nuclease domain and the RNA recognition motif. The R349W mutation was inherited from the unaffected father, whereas the intragenic deletion was inherited from the mother who had an unspecified mental illness requiring admission to a psychiatric ward. The R349W mutation was not found in over 2,000 control individuals, but it was reported at a low frequency (8.32 x 10(-6)) in the ExAC database. Patient cells showed significantly decreased PARN mRNA levels, suggesting that the deletion resulted in nonsense-mediated mRNA decay. PARN protein levels were also decreased. In vitro functional expression studies showed that the R349W mutant protein had markedly reduced deadenylation activity (about 50%) compared to wildtype. Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (602322), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects. </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>.0010 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 6</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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PARN, 22-KB DEL
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<br />
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ClinVar: RCV000203556
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>For discussion of the 22-kb deletion (c.919_1262del344) in the PARN gene that was found in compound heterozygous state in a patient with a severe form of autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome by Dhanraj et al. (2015), see 604212.0009. </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>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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<p class="mim-text-font">
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|
Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others.
|
|
<strong>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).</strong>
|
|
J. Med. Genet. 52: 738-748, 2015.
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[PubMed: 26342108]
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[Full Text: https://doi.org/10.1136/jmedgenet-2015-103292]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Korner, C. G., Wahle, E.
|
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<strong>Poly(A) tail shortening by a mammalian poly(A)-specific 3-prime-exoribonuclease.</strong>
|
|
J. Biol. Chem. 272: 10448-10456, 1997.
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[PubMed: 9099687]
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[Full Text: https://doi.org/10.1074/jbc.272.16.10448]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Korner, C. G., Wormington, M., Muckenthaler, M., Schneider, S., Dehlin, E., Wahle, E.
|
|
<strong>The deadenylating nuclease (DAN) is involved in poly(A) tail removal during the meiotic maturation of Xenopus oocytes.</strong>
|
|
EMBO J. 17: 5427-5437, 1998.
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[PubMed: 9736620]
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[Full Text: https://doi.org/10.1093/emboj/17.18.5427]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Moon, D. H., Segal, M., Boyraz, B., Guinan, E., Hofmann, I., Cahan, P., Tai, A. K., Agarwal, S.
|
|
<strong>Poly(A)-specific ribonuclease (PARN) mediates 3-prime-end maturation of the telomerase RNA component.</strong>
|
|
Nature Genet. 47: 1482-1488, 2015.
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|
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|
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[PubMed: 26482878]
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[Full Text: https://doi.org/10.1038/ng.3423]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others.
|
|
<strong>Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.</strong>
|
|
Nature Genet. 47: 512-517, 2015.
|
|
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|
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[PubMed: 25848748]
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[Full Text: https://doi.org/10.1038/ng.3278]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I.
|
|
<strong>Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.</strong>
|
|
J. Clin. Invest. 125: 2151-2160, 2015.
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|
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[PubMed: 25893599]
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[Full Text: https://doi.org/10.1172/JCI78963]
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</p>
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</li>
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</ol>
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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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<div class="row">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</div>
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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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Ada Hamosh - updated : 02/08/2016<br>Cassandra L. Kniffin - updated : 1/7/2016<br>Cassandra L. Kniffin - updated : 5/18/2015<br>Cassandra L. Kniffin - updated : 5/11/2015<br>Patti M. Sherman - updated : 10/5/1999
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</span>
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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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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Barbara J. Biery : 9/30/1999
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</span>
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</div>
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</div>
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<br />
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Edit History:
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<span class="mim-text-font">
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alopez : 05/10/2023<br>alopez : 05/08/2023<br>alopez : 05/08/2023<br>alopez : 02/08/2016<br>carol : 1/12/2016<br>ckniffin : 1/7/2016<br>alopez : 9/18/2015<br>carol : 5/20/2015<br>mcolton : 5/18/2015<br>ckniffin : 5/18/2015<br>carol : 5/13/2015<br>carol : 5/12/2015<br>mcolton : 5/11/2015<br>ckniffin : 5/11/2015<br>carol : 3/21/2014<br>mgross : 3/14/2000<br>mgross : 10/5/1999<br>psherman : 10/5/1999<br>psherman : 10/1/1999
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