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Entry
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- *602322 - TELOMERASE RNA COMPONENT; TERC
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602322</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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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602322">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000277925;t=ENST00000363312" 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=7012" 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=602322" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<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=ENSG00000277925;t=ENST00000363312" 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</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NR_001566" 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://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=602322" 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://www.proteinatlas.org/search/TERC" 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>
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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=7012" 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=ENSG00000277925;t=ENST00000363312" 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=TERC" 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=TERC" 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+7012" 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/TERC" 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:7012" 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/7012" 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=chr3&hgg_gene=ENST00000602385.2&hgg_start=169764610&hgg_end=169765060&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11727" 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=602322[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 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=602322[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/TERC/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/ENSG00000277925" 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.gwascentral.org/search?q=TERC" 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=TERC" 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="http://telomerase.asu.edu/diseases.html#tr" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TERC&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/PA36444" 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:11727" 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="http://v1.marrvel.org/search/gene/TERC#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="https://www.ncbi.nlm.nih.gov/gene/7012/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=7012" 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>
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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:7012" 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>
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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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602322
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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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TELOMERASE RNA COMPONENT; TERC
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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TELOMERASE RNA CANDIDATE 3; TRC3<br />
|
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TR
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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=TERC" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TERC</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/3/848?start=-3&limit=10&highlight=848">3q26.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:169764610-169765060&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'})">3:169,764,610-169,765,060</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=127550,614743" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
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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>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
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<a href="/geneMap/3/848?start=-3&limit=10&highlight=848">
|
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3q26.2
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Dyskeratosis congenita, autosomal dominant 1
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/127550"> 127550 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</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>
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<span class="mim-font">
|
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614743"> 614743 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/602322" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/602322" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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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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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
|
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<p>Eukaryotic chromosomes are capped with repetitive telomere sequences that protect the ends from damage and rearrangements. Telomere repeats are synthesized by telomerase, an enzyme that has both a catalytic (TERT; <a href="/entry/187270">187270</a>) and an RNA component. The RNA component acts as a template for the addition of telomeric repeat sequences (<a href="#15" class="mim-tip-reference" title="Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., Avilion, A. A., Chiu, C.-P., Adams, R. R., Chang, E., Allsopp, R. C., Yu, J., Le, S., West, M. D., Harley, C. B., Andrews, W. H., Greider, C. W., Villeponteau, B. <strong>The RNA component of human telomerase.</strong> Science 269: 1236-1241, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544491</a>] [<a href="https://doi.org/10.1126/science.7544491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7544491">Feng et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7544491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<br />
|
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</div>
|
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</div>
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p><a href="#15" class="mim-tip-reference" title="Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., Avilion, A. A., Chiu, C.-P., Adams, R. R., Chang, E., Allsopp, R. C., Yu, J., Le, S., West, M. D., Harley, C. B., Andrews, W. H., Greider, C. W., Villeponteau, B. <strong>The RNA component of human telomerase.</strong> Science 269: 1236-1241, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544491</a>] [<a href="https://doi.org/10.1126/science.7544491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7544491">Feng et al. (1995)</a> cloned the 451-nucleotide gene for the telomerase RNA component, which they designated TRC3. TRC3 copurified with telomerase. TRC3 was highly expressed in the germline and in tumor cell lines, which had high telomerase activity, and at lower levels in kidney, prostate, and liver, which had no detectable telomerase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7544491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Soder, A. I., Hoare, S. F., Muire, S., Balmain, A., Parkinson, E. K., Keith, W. N. <strong>Mapping of the gene for the mouse telomerase RNA component, Terc, to chromosome 3 by fluorescence in situ hybridization and mouse chromosome painting.</strong> Genomics 41: 293-294, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143511</a>] [<a href="https://doi.org/10.1006/geno.1997.4621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143511">Soder et al. (1997)</a> mapped the mouse Terc gene to chromosome 3 and, based on syntenic homology with human chromosomes, suggested that the human TERC gene is located on 3q21-q28. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9143511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., Avilion, A. A., Chiu, C.-P., Adams, R. R., Chang, E., Allsopp, R. C., Yu, J., Le, S., West, M. D., Harley, C. B., Andrews, W. H., Greider, C. W., Villeponteau, B. <strong>The RNA component of human telomerase.</strong> Science 269: 1236-1241, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544491</a>] [<a href="https://doi.org/10.1126/science.7544491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7544491">Feng et al. (1995)</a> found that HeLa cells transfected with antisense TRC3 lost telomeric DNA and began to die after 23 to 26 divisions, showing that telomerase is critical for the long-term proliferation of tumor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7544491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Inhibition or activation of the reverse transcriptase telomerase can profoundly affect the proliferative capacity of normal cells and cancers. <a href="#24" class="mim-tip-reference" title="Mitchell, J. R., Collins, K. <strong>Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase.</strong> Molec. Cell 6: 361-371, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10983983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10983983</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00036-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10983983">Mitchell and Collins (2000)</a> elucidated structural requirements for function of the essential RNA component of human telomerase, TR. Two motifs within the independently stable H/ACA domain of TR are required for accumulation of the mature RNA in vivo. However, these motifs can be substituted by a heterologous H/ACA family RNA. Two additional TR elements are required both in vivo and in vitro for telomerase catalytic activity. Surprisingly, these elements independently bind the telomerase reverse transcriptase. The results established fundamental differences between vertebrate and ciliate telomerase ribonucleoprotein architectures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10983983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Mitchell, J. R., Wood, E., Collins, K. <strong>A telomerase component is defective in the human disease dyskeratosis congenita.</strong> Nature 402: 551-555, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10591218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10591218</a>] [<a href="https://doi.org/10.1038/990141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10591218">Mitchell et al. (1999)</a> demonstrated that dyskerin (<a href="/entry/300126">300126</a>) is associated not only with H/ACA small nucleolar RNAs but also with human telomerase RNA, which contains an H/ACA RNA motif. They found that primary fibroblasts and lymphoblasts from dyskeratosis congenita (DKC; <a href="/entry/305000">305000</a>)-affected males were not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function. However, DKC cells had a lower level of telomerase RNA, produced lower levels of telomerase activity than matched normal cells, and had shorter telomeres. <a href="#25" class="mim-tip-reference" title="Mitchell, J. R., Wood, E., Collins, K. <strong>A telomerase component is defective in the human disease dyskeratosis congenita.</strong> Nature 402: 551-555, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10591218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10591218</a>] [<a href="https://doi.org/10.1038/990141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10591218">Mitchell et al. (1999)</a> concluded that the pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10591218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="de Lange, T., Jacks, T. <strong>For better or worse? Telomerase inhibition and cancer.</strong> Cell 98: 273-275, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10458601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10458601</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81955-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10458601">De Lange and Jacks (1999)</a> provided a comprehensive review of the status of knowledge concerning the biologic importance of TERC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10458601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Okuda, K., Bardeguez, A., Gardner, J. P., Rodriguez, P., Ganesh, V., Kimura, M., Skurnick, J., Awad, G., Aviv, A. <strong>Telomere length in the newborn.</strong> Pediat. Res. 52: 377-381, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193671</a>] [<a href="https://doi.org/10.1203/00006450-200209000-00012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193671">Okuda et al. (2002)</a> found no evidence for gender effect on telomere length at birth and suggested that the longer length of telomeres in women is due to a slower rate of telomere shortening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12193671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Cohen, S. B., Graham, M. E., Lovrecz, G. O., Bache, N., Robinson, P. J., Reddel, R. R. <strong>Protein composition of catalytically active human telomerase from immortal cells.</strong> Science 315: 1850-1853, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17395830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17395830</a>] [<a href="https://doi.org/10.1126/science.1138596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17395830">Cohen et al. (2007)</a> purified human telomerase 10(8)-fold, with the final elution dependent on the enzyme's ability to catalyze nucleotide addition onto a DNA oligonucleotide of telomeric sequence, thereby providing specificity for catalytically active telomerase. Mass spectrometric sequencing of the protein components and molecular size determination indicated an enzyme composition of 2 molecules each of telomerase reverse transcriptase (TERT; <a href="/entry/187270">187270</a>) and TERC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17395830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Cristofari, G., Adolf, E., Reichenbach, P., Sikora, K., Terns, R. M., Terns, M. P., Lingner, J. <strong>Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation.</strong> Molec. Cell 27: 882-889, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17889662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17889662</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17889662">Cristofari et al. (2007)</a> stated that telomerase accumulates in Cajal bodies (CBs) and that this localization relies on a CAB box motif (UGAG) within the loop of a stem-loop structure of TERC. They found that mutations of the CAB box of human TERC that impaired accumulation of telomerase in CBs did not affect telomerase catalytic activity in vivo, but they decreased association of telomerase with telomeres and impaired telomere extension in human cells. <a href="#13" class="mim-tip-reference" title="Cristofari, G., Adolf, E., Reichenbach, P., Sikora, K., Terns, R. M., Terns, M. P., Lingner, J. <strong>Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation.</strong> Molec. Cell 27: 882-889, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17889662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17889662</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17889662">Cristofari et al. (2007)</a> concluded that localization of telomerase within CBs is required to maintain telomere length. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17889662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Box, J. A., Bunch, J. T., Tang, W., Baumann, P. <strong>Spliceosomal cleavage generates the 3-prime end of telomerase RNA.</strong> Nature 456: 910-914, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19052544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19052544</a>] [<a href="https://doi.org/10.1038/nature07584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19052544">Box et al. (2008)</a> showed that in Schizosaccharomyces pombe telomerase RNA transcripts must be processed to generate functional telomerase. Characterization of the maturation pathway uncovered an unexpected role for the spliceosome, which normally catalyzes splicing of pre-messenger RNA. The first spliceosomal cleavage reaction generates the mature 3-prime end of telomerase RNA (TER1, the functional RNA encoded by the ter1+ gene), releasing the active form of the RNA without exon ligation. Blocking the first step or permitting completion of splicing generates inactive forms of TER1 and causes progressive telomere shortening. <a href="#10" class="mim-tip-reference" title="Box, J. A., Bunch, J. T., Tang, W., Baumann, P. <strong>Spliceosomal cleavage generates the 3-prime end of telomerase RNA.</strong> Nature 456: 910-914, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19052544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19052544</a>] [<a href="https://doi.org/10.1038/nature07584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19052544">Box et al. (2008)</a> established that 3-prime end processing of TER1 is critical for telomerase function and described a theretofore unknown mechanism for RNA maturation that uses the ability of the spliceosome to mediate site-specific cleavage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19052544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Venteicher, A. S., Abreu, E. B., Meng, Z., McCann, K. E., Terns, R. M., Veenstra, T. D., Terns, M. P., Artandi, S. E. <strong>A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis.</strong> Science 323: 644-648, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19179534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19179534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19179534[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19179534">Venteicher et al. (2009)</a> found that TCAB1 (<a href="/entry/612661">612661</a>) associates with TERT, established telomerase components dyskerin (<a href="/entry/300126">300126</a>) and TERC, and small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevented TERC from associating with Cajal bodies, disrupted telomerase-telomere association, and abrogated telomere synthesis in telomerase. Thus, <a href="#35" class="mim-tip-reference" title="Venteicher, A. S., Abreu, E. B., Meng, Z., McCann, K. E., Terns, R. M., Veenstra, T. D., Terns, M. P., Artandi, S. E. <strong>A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis.</strong> Science 323: 644-648, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19179534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19179534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19179534[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19179534">Venteicher et al. (2009)</a> concluded that TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19179534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A cardinal feature of induced pluripotent stem cells (iPS) is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene TERT. <a href="#1" class="mim-tip-reference" title="Agarwal, S., Loh, Y.-H., McLoughlin, E. M., Huang, J., Park, I-H., Miller, J. D., Huo, H., Okuka, M., dos Reis, R. M., Loewer, S., Hg, H.-H., Keefe, D. L., Goldman, F. D., Klingelhutz, A. J., Liu, L., Daley, G. Q. <strong>Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.</strong> Nature 464: 292-296, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20164838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20164838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20164838[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/nature08792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20164838">Agarwal et al. (2010)</a> investigated whether defects in telomerase function would limit derivation maintenance of iPS cells from patients with dyskeratosis congenita (DKC; see <a href="/entry/127550">127550</a>). The authors showed that reprogrammed dendritic congenita cells overcome a critical limitation in TERC levels to restore telomere maintenance and self-renewal. <a href="#1" class="mim-tip-reference" title="Agarwal, S., Loh, Y.-H., McLoughlin, E. M., Huang, J., Park, I-H., Miller, J. D., Huo, H., Okuka, M., dos Reis, R. M., Loewer, S., Hg, H.-H., Keefe, D. L., Goldman, F. D., Klingelhutz, A. J., Liu, L., Daley, G. Q. <strong>Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.</strong> Nature 464: 292-296, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20164838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20164838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20164838[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/nature08792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20164838">Agarwal et al. (2010)</a> discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DKC, transcriptional silencing accompanies a 3-prime deletion at the TERC locus. <a href="#1" class="mim-tip-reference" title="Agarwal, S., Loh, Y.-H., McLoughlin, E. M., Huang, J., Park, I-H., Miller, J. D., Huo, H., Okuka, M., dos Reis, R. M., Loewer, S., Hg, H.-H., Keefe, D. L., Goldman, F. D., Klingelhutz, A. J., Liu, L., Daley, G. Q. <strong>Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.</strong> Nature 464: 292-296, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20164838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20164838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20164838[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/nature08792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20164838">Agarwal et al. (2010)</a> concluded that their results demonstrated that reprogramming restores telomere elongation in DKC cells despite genetic lesions affecting telomerase, and showed that strategies to increase TERC expression may be therapeutically beneficial in DKC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20164838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 (<a href="/entry/604212">604212</a>) mutations, <a href="#26" 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 TERC. 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. <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 Dominant Dyskeratosis Congenita 1</em></strong></p><p>
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<a href="#37" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., Dokal, I. <strong>The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.</strong> Nature 413: 432-435, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11574891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11574891</a>] [<a href="https://doi.org/10.1038/35096585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11574891">Vulliamy et al. (2001)</a> identified 3 different mutations in TERC in 3 families segregating autosomal dominant dyskeratosis congenita-1 (DKCA1; <a href="/entry/127550">127550</a>). The first mutation (<a href="#0001">602322.0001</a>) resulted in an 821-bp deletion including the 74 3-prime basepairs of the coding region. The deleted region is flanked by a 4-bp direct repeat, AGGA. Lymphocyte cell lines derived from affected individuals in this family were examined by Northern blot analysis. No difference was found between cell lines from affected and unaffected individuals; however, RT-PCR using a mutant-specific 3-prime primer abutting the point of the deletion showed that the mutant transcript is barely detectable. Telomere length in affected family members was significantly shorter than in normal patients, even in young children with manifestation of disease. The second mutation was a single-basepair substitution at nucleotide 408 (<a href="#0002">602322.0002</a>). This mutation did not affect transcript levels, but is predicted to destabilize the stem structure in the CR7 domain. A third family had a 2-bp substitution at nucleotides 107 to 108 (<a href="#0003">602322.0003</a>). This mutation also did not affect transcript levels but appears to destabilize a hairpin stem region in the pseudoknot region of the proposed secondary structure of TERC. This region is essential for telomerase activity and seems to be involved in interaction with telomere reverse transcriptase (TERT; <a href="/entry/187270">187270</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11574891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Theimer, C. A., Finger, L. D., Trantirek, L., Feigon, J. <strong>Mutations linked to dyskeratosis congenita cause changes in the structural equilibrium in telomerase RNA.</strong> Proc. Nat. Acad. Sci. 100: 449-454, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12525685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12525685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12525685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.242720799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12525685">Theimer et al. (2003)</a> demonstrated that mutations in the TERC gene that result in autosomal dominant dyskeratosis congenita cause changes in the structural equilibrium of RNA polymerase. They reported structural and thermodynamic studies of wildtype and mutant human telomerase subdomains that provided 3D structural insight into the molecular basis of the disease. The work revealed the presence of a phylogenetically conserved hairpin in equilibrium with a pseudoknot in the telomerase pseudoknot domain, which is stabilized by a unique uridine helix. <a href="#34" class="mim-tip-reference" title="Theimer, C. A., Finger, L. D., Trantirek, L., Feigon, J. <strong>Mutations linked to dyskeratosis congenita cause changes in the structural equilibrium in telomerase RNA.</strong> Proc. Nat. Acad. Sci. 100: 449-454, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12525685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12525685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12525685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.242720799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12525685">Theimer et al. (2003)</a> proposed that interconversion between the hairpin and pseudoknot conformations is functionally important, and that pseudoknot mutations in dyskeratosis congenita affect this interconversion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12525685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Szydlo, R., Walne, A., Mason, P. J., Dokal, I. <strong>Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.</strong> Nature Genet. 36: 447-449, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15098033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15098033</a>] [<a href="https://doi.org/10.1038/ng1346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15098033">Vulliamy et al. (2004)</a> demonstrated that anticipation occurs in autosomal dominant dyskeratosis congenita and that the molecular basis resides in progressive telomere shortening in successive generations. In 8 families, the disease became more severe in succeeding generations. Of affected parents, 7 of 12 were asymptomatic, ranging in age from 36 to 61 years. In these cases, dyskeratosis congenita was diagnosed only by the identification of a TERC mutation; subtle signs of the disease were often detected subsequently. For the 5 remaining affected parents, the median age at which disease features were first identified was 37 years. Of the affected children, only 5 of 15 remained asymptomatic; they were aged 3, 7, 11, 14, and 20 years and were diagnosed only through mutation analysis. For the remaining 10 affected children, symptoms presented at a median age of 14.5 years. <a href="#38" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Szydlo, R., Walne, A., Mason, P. J., Dokal, I. <strong>Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.</strong> Nature Genet. 36: 447-449, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15098033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15098033</a>] [<a href="https://doi.org/10.1038/ng1346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15098033">Vulliamy et al. (2004)</a> also observed a number of individuals who had a bimodal distribution of telomere length. A bimodal distribution had previously been observed in human fibroblast cell lines where the short and long telomeres were linked to maternal and paternal alleles. The difference in telomere length between the 2 alleles seemed to be maintained from the zygote throughout development (<a href="#6" class="mim-tip-reference" title="Baird, D. M., Rowson, J., Wynford-Thomas, D., Kipling, D. <strong>Extensive allelic variation and ultrashort telomeres in senescent human cells.</strong> Nature Genet. 33: 203-207, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539050</a>] [<a href="https://doi.org/10.1038/ng1084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12539050">Baird et al., 2003</a>). Thus, another mechanism was added to the phenomenon of disease anticipation. The only convincing mechanism theretofore described involved expansion of triplet repeats as observed in several neurodegenerative disorders. There are clear analogies here with Terc knockout mice: parental mice have very long telomeres, and in the first generation, Terc -/- mice are asymptomatic. Features of telomere shortening, which overlap the clinical features seen in dyskeratosis congenita, develop only in the fourth generation. By the sixth generation, these mice become infertile. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15098033+12539050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Goldman, F., Bouarich, R., Kulkarni, S., Freeman, S., Du, H.-Y., Harrington, L., Mason, P. J., Londono-Vallejo, A., Bessler, M. <strong>The effect of TERC haploinsufficiency on the inheritance of telomere length.</strong> Proc. Nat. Acad. Sci. 102: 17119-17124, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16284252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16284252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16284252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505318102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16284252">Goldman et al. (2005)</a> studied telomere dynamics over 3 generations in a 32-member extended family with autosomal dominant dyskeratosis congenita due to TERC gene deletion. They found that in gene deletion carriers, paternal and maternal telomeres were similarly short and similar in length to those of the affected parent. In children of affected parents who had normal TERC genes, parental telomeres were again similar in length, but 2 generations appeared to be necessary to fully restore normal telomere length. <a href="#17" class="mim-tip-reference" title="Goldman, F., Bouarich, R., Kulkarni, S., Freeman, S., Du, H.-Y., Harrington, L., Mason, P. J., Londono-Vallejo, A., Bessler, M. <strong>The effect of TERC haploinsufficiency on the inheritance of telomere length.</strong> Proc. Nat. Acad. Sci. 102: 17119-17124, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16284252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16284252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16284252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505318102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16284252">Goldman et al. (2005)</a> concluded that these results were consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting, this preference leads to the accelerated shortening of longer telomeres. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16284252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Jongmans, M. C. J., Verwiel, E. T. P., Heijdra, Y., Vulliamy, T., Kamping, E. J., Hehir-Kwa, J. Y., Bongers, E. M. H. F., Pfundt, R., van Emst, L., van Leeuwen, F. N., van Gassen, K. L. I., Geurts van Kessel, A., Dokal, I., Hoogerbrugge, N., Ligtenberg, M. J. L., Kuiper, R. P. <strong>Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita.</strong> Am. J. Hum. Genet. 90: 426-433, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22341970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22341970</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22341970[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.01.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22341970">Jongmans et al. (2012)</a> observed somatic reversion of the mutant TERC allele in blood cells of 2 affected members of a family with variable manifestations of DKCA1 due to a heterozygous germline TERC mutation (<a href="#0011">602322.0011</a>). In both cases, the reversion occurred by acquired uniparental disomy of chromosome 3q, including TERC, during mitotic recombination. Four additional cases of a mosaic-reversion pattern in blood cells were found among a cohort of 17 patients with germline TERC mutations. None of the patients with somatic mosaic reversion had bone marrow failure, and all had a small deletion in the TERC gene. The findings indicated that revertant somatic mosaicism is a recurrent event in DKCA1, which has important implications for diagnostic testing, often performed on blood cells, and may help explain the variable phenotype of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22341970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2</em></strong></p><p>
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Bone marrow failure in X-linked dyskeratosis congenita is caused by mutations in the nucleolar protein dyskerin. This protein binds to a particular class of small nucleolar RNAs called H/ACA as well as to telomerase RNA. As discussed above, the very rare autosomal dominant form of dyskeratosis congenita is caused by mutations in the RNA component of telomerase, encoded by the TERC gene, and such patients consequently have very short telomeres (<a href="#37" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., Dokal, I. <strong>The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.</strong> Nature 413: 432-435, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11574891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11574891</a>] [<a href="https://doi.org/10.1038/35096585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11574891">Vulliamy et al., 2001</a>). Patients with idiopathic aplastic anemia and bone marrow failure (see PFBMFT2, <a href="/entry/614743">614743</a>) also have shorter telomeres than normal controls (<a href="#7" class="mim-tip-reference" title="Ball, S. E., Gibson, F. M., Rizzo, S., Tooze, J. A., Marsh, J. C. W., Gordon-Smith, E. C. <strong>Progressive telomere shortening in aplastic anemia.</strong> Blood 91: 3582-3592, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9572992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9572992</a>]" pmid="9572992">Ball et al., 1998</a>). This prompted <a href="#36" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. <strong>Association between aplastic anaemia and mutations in telomerase RNA.</strong> Lancet 359: 2168-2170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12090986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12090986</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12090986">Vulliamy et al. (2002)</a> to perform mutation screens of the TERC gene in patients with aplastic anemia. They identified TERC mutations in 2 of 17 patients with idiopathic aplastic anemia, in 3 of 27 patients with constitutional aplastic anemia, and in none of 214 normal controls. Furthermore, patients with TERC mutations had significantly shorter telomeres than age-matched controls. These data indicated that in a subset of patients with aplastic anemia, the disorder may be associated with a genetic lesion in the telomere maintenance pathway. Mutations were heterozygous in each case. The c.58G-A mutation (<a href="#0004">602322.0004</a>) was found in 3 of the patients, 2 of whom were categorized as having idiopathic aplastic anemia and 1 as having constitutional aplastic anemia (associated with short stature and phimosis). The age at first clinical presentation in these 3 patients varied from 5 to 53 years. This variability in the severity and age of onset in patients with the same mutation highlighted the role of other genetic or environmental factors in the clinical phenotype. <a href="#36" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. <strong>Association between aplastic anaemia and mutations in telomerase RNA.</strong> Lancet 359: 2168-2170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12090986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12090986</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12090986">Vulliamy et al. (2002)</a> observed that in X-linked dyskeratosis congenita, which is also characterized by aplastic anemia, the recurrent mutation c.1058C-T (<a href="/entry/300126#0006">300126.0006</a>) is associated with a wide variation in the age at onset of aplastic anemia from 1 to 22 years. The constitutional nature of aplastic anemia can sometimes be overlooked. In the patient of <a href="#36" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. <strong>Association between aplastic anaemia and mutations in telomerase RNA.</strong> Lancet 359: 2168-2170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12090986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12090986</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12090986">Vulliamy et al. (2002)</a> with the c.72C-G mutation (<a href="#0005">602322.0005</a>), the presence of pronounced osteoporosis, discovered because of a bone fracture, led to the categorization of constitutional rather than idiopathic disease. Similarly, another patient with a 4-bp deletion in TERC (<a href="#0006">602322.0006</a>) had aplastic anemia alone; he would have been classified as idiopathic if it were not for his sister who also had aplastic anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9572992+12090986+11574891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 families in which an adult was initially diagnosed with acquired aplastic anemia, <a href="#16" class="mim-tip-reference" title="Fogarty, P. F., Yamaguchi, H., Wiestner, A., Baerlocher, G. M., Sloand, E., Zeng, W. S., Read, E. J., Lansdorp, P. M., Young, N. S. <strong>Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA.</strong> Lancet 362: 1628-1630, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14630445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14630445</a>] [<a href="https://doi.org/10.1016/S0140-6736(03)14797-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14630445">Fogarty et al. (2003)</a> detected novel point mutations in the TERC gene in affected members of both families: a heterozygous c.116C-T transition (<a href="#0007">602322.0007</a>) in 1 family, and a heterozygous c.204C-G transversion (<a href="#0008">602322.0008</a>) in the other. Affected members of both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14630445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Armanios, M. Y., Chen, J. J.-L., Cogan, J. D., Alder, J. K., Ingersoll, R. G., Markin, C., Lawson, W. E., Xie, M., Vulto, I., Phillips, J. A., III, Lansdorp, P. M., Greider, C. W., Loyd, J. E. <strong>Telomerase mutations in families with idiopathic pulmonary fibrosis.</strong> New Eng. J. Med. 356: 1317-1326, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17392301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17392301</a>] [<a href="https://doi.org/10.1056/NEJMoa066157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17392301">Armanios et al. (2007)</a> screened 73 probands with familial idiopathic pulmonary fibrosis for mutations in the TERT or TERC genes and identified 5 mutations in TERT (see, e.g., <a href="/entry/187270#0010">187270.0010</a>) and 1 in TERC (<a href="#0009">602322.0009</a>) in 6 probands, respectively. Average telomere length was significantly less in probands and asymptomatic mutation carriers than in relatives who did not carry the mutation (p = 0.006), suggesting that asymptomatic carriers may also be at risk for the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17392301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Alder, J. K., Chen, J. J.-L., Lancaster, L., Danoff, S., Su, S., Cogan, J. D., Vulto, I., Xie, M., Qi, X., Tuder, R. M., Phillips, J. A., III, Lansdorp, P. M., Loyd, J. E., Armanios, M. Y. <strong>Short telomeres are a risk factor for idiopathic pulmonary fibrosis.</strong> Proc. Nat. Acad. Sci. 105: 13051-13056, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18753630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18753630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18753630[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0804280105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18753630">Alder et al. (2008)</a> screened 100 consecutive patients with sporadic idiopathic interstitial pneumonia, the majority of whom had been diagnosed with idiopathic pulmonary fibrosis, for mutations in the TERT and TERC genes and identified a mutation in 1 patient (<a href="#0010">602322.0010</a>) that was associated with short telomeres, led to a loss of activity, and was not found in 194 healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18753630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Telomerase RNA Pseudoknot Domain</em></strong></p><p>
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Mutations causing autosomal dominant dyskeratosis congenita and aplastic anemia include base changes in a highly conserved putative telomerase RNA pseudoknot. <a href="#12" class="mim-tip-reference" title="Comolli, L. R., Smirnov, I., Xu, L., Blackburn, E. H., James, T. L. <strong>A molecular switch underlies a human telomerase disease.</strong> Proc. Nat. Acad. Sci. 99: 16998-17003, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12482936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12482936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12482936[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.262663599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12482936">Comolli et al. (2002)</a> described functional, structural, and energetic properties of this structure. They demonstrated that the pseudoknot domain exists in 2 alternative states of nearly equal stability in solution: a structured P2b loop domain and the pseudoknot formed by its pairing with P3. They showed that a 2-base mutation, 107GC-108AG (<a href="#0003">602322.0003</a>), in 1 gene copy in a family with dyskeratosis congenita abrogated telomerase activity. This mutation hyperstabilizes the P2b intraloop structure, blocking pseudoknot formation. Conversely, when the P3 pseudoknot pairing is hyperstabilized by deleting a conserved bulge in P3, telomerase activity also decreases. <a href="#12" class="mim-tip-reference" title="Comolli, L. R., Smirnov, I., Xu, L., Blackburn, E. H., James, T. L. <strong>A molecular switch underlies a human telomerase disease.</strong> Proc. Nat. Acad. Sci. 99: 16998-17003, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12482936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12482936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12482936[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.262663599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12482936">Comolli et al. (2002)</a> proposed that the P2b/P3 pseudoknot domain acts as a molecular switch, and interconversion between its 2 states is important for telomerase function. Phylogenetic covariation in the P2b and P3 sequences of 35 species provided a compelling set of 'natural' compensatory basepairing changes supporting the existence of the crucial molecular switch. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12482936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between mean leukocyte telomere length and genetic variation near the TERC locus, see <a href="/entry/609113">609113</a>.</p>
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<p><a href="#23" class="mim-tip-reference" title="Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., II, Greider, C. W., DePinho, R. A. <strong>Essential role of mouse telomerase in highly proliferative organs.</strong> Nature 392: 569-574, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9560153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9560153</a>] [<a href="https://doi.org/10.1038/33345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9560153">Lee et al. (1998)</a> investigated the role of the enzyme telomerase in highly proliferative organs in successive generations of mice lacking telomerase RNA. Late-generation animals exhibited defective spermatogenesis, with increased programmed cell death (apoptosis) and decreased proliferation in the testis. Proliferative capacity of hematopoietic cells in the bone marrow and spleen was also compromised. These progressively adverse effects coincided with substantial erosion of telomeres and fusion and loss of chromosomes. These findings indicated an essential role for telomerase, and hence telomeres, in the maintenance of genomic integrity and in the long-term viability of high-renewal organ systems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9560153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To examine the role of telomerase in normal and neoplastic growth, <a href="#9" class="mim-tip-reference" title="Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., Greider, C. W. <strong>Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.</strong> Cell 91: 25-34, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9335332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9335332</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)80006-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9335332">Blasco et al. (1997)</a> deleted the telomerase RNA component from the mouse germline. Terc -/- mice lacked detectable telomerase activity yet were viable for the 6 generations analyzed. Telomerase-deficient cells could be immortalized in culture and transformed by viral oncogenes, and generated tumors in nude mice following transformation. Telomeres were shown to shorten at a rate of 4.8 +/- 2.4 kb per Terc -/- generation. Cells from the fourth Terc -/- generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions. These results indicated that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9335332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To examine the role of telomerase in telomere maintenance and cellular viability, <a href="#27" class="mim-tip-reference" title="Niida, H., Matsumoto, T., Satoh, H., Shiwa, M., Tokutake, Y., Furuichi, Y., Shinkai, Y. <strong>Severe growth defect in mouse cells lacking the telomerase RNA component.</strong> Nature Genet. 19: 203-206, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620783</a>] [<a href="https://doi.org/10.1038/580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620783">Niida et al. (1998)</a> established Terc-deficient embryonic stem (ES) cells. It had been known that telomerase activity is absent in cells from Terc knockout mice. Although telomere shortening had been observed in the Terc-deficient cells from first to sixth generation animals, whether telomerase-dependent telomere maintenance was essential for cellular viability remained to be elucidated. <a href="#27" class="mim-tip-reference" title="Niida, H., Matsumoto, T., Satoh, H., Shiwa, M., Tokutake, Y., Furuichi, Y., Shinkai, Y. <strong>Severe growth defect in mouse cells lacking the telomerase RNA component.</strong> Nature Genet. 19: 203-206, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620783</a>] [<a href="https://doi.org/10.1038/580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620783">Niida et al. (1998)</a> examined Terc-deficient ES cells under long-term culture conditions. During their continual telomere shortening, the growth rate of Terc-deficient ES cells was gradually reduced after more than 300 divisions. An impaired growth rate was maintained to approximately 450 divisions, and then cell growth virtually stopped. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Rudolph, K. L., Chang, S., Lee, H.-W., Blasco, M., Gottlieb, G. J., Greider, C., DePinho, R. A. <strong>Longevity, stress response, and cancer in aging telomerase-deficient mice.</strong> Cell 96: 701-712, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10089885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10089885</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80580-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10089885">Rudolph et al. (1999)</a> studied a variety of physiologic processes in an aging cohort of Terc -/- mice. Loss of telomere function did not elicit a full spectrum of classic pathophysiologic symptoms of aging. Age-dependent telomere shortening and accompanying genetic instability were, however, associated with shortened life span, as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, the authors found an increased incidence of spontaneous malignancies. These findings demonstrated a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10089885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., DePinho, R. A. <strong>Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.</strong> Nature 406: 641-645, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10949306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10949306</a>] [<a href="https://doi.org/10.1038/35020592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10949306">Artandi et al. (2000)</a> monitored the cancer phenotype and cytogenetics of large cohorts of telomerase-deficient p53 (<a href="/entry/191170">191170</a>) mutant mice. Mice lacking the RNA component of telomerase (mTERC) exhibit progressive telomere shortening and ultimately chromosomal instability (end-to-end fusions) as a function of age and of successive generational matings. In generation 1 and 2 mTERC -/- p53 -/- mice that lacked telomerase but retained normal telomere function, median tumor incidence was similar to that of mTERC +/+ p53 -/- and mTERC +/- p53 -/- controls. In contrast, in later generations the progressive decline in telomere function correlated with decreasing tumor latency. Similarly, in p53 +/- cohorts, median tumor latency decreased progressively as telomeres became short and dysfunctional. Telomere attrition in aging telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex nonreciprocal translocations - a classic cytogenetic feature of human carcinomas. <a href="#5" class="mim-tip-reference" title="Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., DePinho, R. A. <strong>Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.</strong> Nature 406: 641-645, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10949306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10949306</a>] [<a href="https://doi.org/10.1038/35020592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10949306">Artandi et al. (2000)</a> concluded that their data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10949306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Wong, K.-K., Chang, S., Weiler, S. R., Ganesan, S., Chaudhuri, J., Zhu, C., Artandi, S. E., Rudolph, K. L., Gottlieb, G. J., Chin, L., Alt, F. W., DePinho, R. A. <strong>Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation.</strong> Nature Genet. 26: 85-88, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973255</a>] [<a href="https://doi.org/10.1038/79232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973255">Wong et al. (2000)</a> used the telomerase-deficient mouse, null for the telomerase RNA gene, Terc, to assess the role of telomerase and telomere function in the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernible impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc -/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks, and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Inhibition of telomerase has been proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumor cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumor growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumor therapy, as its inhibition is unlikely to have toxic effects. <a href="#18" class="mim-tip-reference" title="Gonzalez-Suarez, E., Samper, E., Flores, J. M., Blasco, M. A. <strong>Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis.</strong> Nature Genet. 26: 114-117, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973262</a>] [<a href="https://doi.org/10.1038/79089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973262">Gonzalez-Suarez et al. (2000)</a> showed that late-generation Terc -/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumor development in multistage skin carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the processes that trigger cellular responses to telomere dysfunction, <a href="#19" class="mim-tip-reference" title="Hemann, M. T., Strong, M. A., Hao, L.-Y., Greider, C. W. <strong>The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.</strong> Cell 107: 67-77, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11595186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11595186</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00504-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11595186">Hemann et al. (2001)</a> crossed Tr -/- generation-6 mice that had short telomeres with mice heterozygous for telomerase (Tr +/-) that had long telomeres. The phenotype of the telomerase null offspring was similar to that of the late-generation parent, although only half of the chromosomes were short. Spectral karyotyping analysis revealed that loss of telomere function occurred preferentially on chromosomes with critically short telomeres. These data indicated that it is not the average but rather the shortest telomeres that constitute telomere dysfunction and limit cellular survival in the absence of telomerase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11595186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Wong, K.-K., Maser, R. S., Bachoo, R. M., Menon, J., Carrasco, D. R., Gu, Y., Alt, F. W., DePinho, R. A. <strong>Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.</strong> Nature 421: 643-648, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12540856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12540856</a>] [<a href="https://doi.org/10.1038/nature01385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12540856">Wong et al. (2003)</a> examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and Terc. These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multiorgan system compromise, accelerated aging, and premature death. <a href="#40" class="mim-tip-reference" title="Wong, K.-K., Maser, R. S., Bachoo, R. M., Menon, J., Carrasco, D. R., Gu, Y., Alt, F. W., DePinho, R. A. <strong>Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.</strong> Nature 421: 643-648, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12540856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12540856</a>] [<a href="https://doi.org/10.1038/nature01385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12540856">Wong et al. (2003)</a> showed that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of ataxia-telangiectasia (<a href="/entry/208900">208900</a>) pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12540856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Goldman, F., Bouarich, R., Kulkarni, S., Freeman, S., Du, H.-Y., Harrington, L., Mason, P. J., Londono-Vallejo, A., Bessler, M. <strong>The effect of TERC haploinsufficiency on the inheritance of telomere length.</strong> Proc. Nat. Acad. Sci. 102: 17119-17124, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16284252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16284252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16284252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505318102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16284252">Goldman et al. (2005)</a> noted that there are important differences in telomere maintenance between mouse and human. Compared with humans, laboratory mice have long telomeres. In addition, telomerase is constitutively active in most murine tissues, whereas in humans telomerase activity is greatly diminished in most somatic cells with the exception of stem cells, their immediate progeny, and activated lymphocytes and monocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16284252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Hockemeyer, D., Palm, W., Wang, R. C., Couto, S. S., de Lange, T. <strong>Engineered telomere degradation models dyskeratosis congenita.</strong> Genes Dev. 22: 1773-1785, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550783[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/10.1101/gad.1679208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550783">Hockemeyer et al. (2008)</a> noted that mice lacking components of telomerase fail to show phenotypes typical of DC. They developed a mouse model in which key characteristics of DC were induced by enhanced telomere degradation. Mice lacking the shelterin component Pot1b (<a href="/entry/606478">606478</a>) (Pot1b -/-) and also deficient in Terc (Terc +/-) developed progressive bone marrow failure, hyperpigmentation, and nail abnormalities. Bone marrow failure was fatal between 4 and 5 months of age in Pot1b -/- Terc +/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18550783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Begus-Nahrmann, Y., Lechel, A., Obenauf, A. C., Nalapareddy, K., Peit, E., Hoffmann, E., Schlaudraff, F., Liss, B., Schirmacher, P., Kestler, H., Danenberg, E., Barker, N., Clevers, H., Speicher, M. R., Rudolph, K. L. <strong>p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice.</strong> Nature Genet. 41: 1138-1143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718028</a>] [<a href="https://doi.org/10.1038/ng.426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19718028">Begus-Nahrmann et al. (2009)</a> analyzed the functional consequences of conditional deletion of p53 (<a href="/entry/191170">191170</a>) in late-generation telomerase knockout mice (Terc-null). Intestinal deletion of p53 shortened the life span of telomere-dysfunctional mice without inducing tumor formation. In contrast to deletion of p21 (<a href="/entry/116899">116899</a>), which elongates life span of telomere-dysfunctional mice, the deletion of p53 impaired the depletion of chromosomal-instable intestinal stem cells in aging telomere-dysfunctional mice. These instable stem cells contributed to epithelial regeneration leading to an accumulation of chromosomal instability, increased apoptosis, altered epithelial cell differentiation, and premature intestinal failure. <a href="#8" class="mim-tip-reference" title="Begus-Nahrmann, Y., Lechel, A., Obenauf, A. C., Nalapareddy, K., Peit, E., Hoffmann, E., Schlaudraff, F., Liss, B., Schirmacher, P., Kestler, H., Danenberg, E., Barker, N., Clevers, H., Speicher, M. R., Rudolph, K. L. <strong>p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice.</strong> Nature Genet. 41: 1138-1143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718028</a>] [<a href="https://doi.org/10.1038/ng.426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19718028">Begus-Nahrmann et al. (2009)</a> concluded that their results provided the first experimental evidence for an organ system in which p53-dependent mechanisms prevent tissue destruction in response to telomere dysfunction by depleting genetically instable stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19718028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Armanios, M., Alder, J. K., Parry, E. M., Karim, B., Strong, M. A., Greider, C. W. <strong>Short telomeres are sufficient to cause the degenerative defects associated with aging.</strong> Am. J. Hum. Genet. 85: 823-832, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19944403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19944403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19944403[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.10.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19944403">Armanios et al. (2009)</a> generated wildtype mice with short telomeres. In these mice, <a href="#3" class="mim-tip-reference" title="Armanios, M., Alder, J. K., Parry, E. M., Karim, B., Strong, M. A., Greider, C. W. <strong>Short telomeres are sufficient to cause the degenerative defects associated with aging.</strong> Am. J. Hum. Genet. 85: 823-832, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19944403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19944403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19944403[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.10.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19944403">Armanios et al. (2009)</a> identified hematopoietic and immune defects that resembled those present in patients with dyskeratosis congenita (see <a href="/entry/305000">305000</a>). Patients with dyskeratosis congenita have a premature aging syndrome that can be caused by mutations in the RNA or catalytic component of telomerase (TERC or TERT, <a href="/entry/187270">187270</a>). When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wildtype mice with short telomeres still displayed degenerative defects. <a href="#3" class="mim-tip-reference" title="Armanios, M., Alder, J. K., Parry, E. M., Karim, B., Strong, M. A., Greider, C. W. <strong>Short telomeres are sufficient to cause the degenerative defects associated with aging.</strong> Am. J. Hum. Genet. 85: 823-832, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19944403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19944403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19944403[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.10.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19944403">Armanios et al. (2009)</a> concluded that their findings implicated telomere length as a unique heritable trait and demonstrated that short telomeres are sufficient to mediate the degenerative defects of aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19944403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., and 18 others. <strong>Telomere dysfunction induces metabolic and mitochondrial compromise.</strong> Nature 470: 359-365, 2011. Note: Erratum: Nature 475: 254 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307849[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/nature09787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307849">Sahin et al. (2011)</a> used transcriptomic network analyses in mice null for either Tert or Terc, which exhibit telomere dysfunction, to identify common mechanisms operative in hematopoietic stem cells, heart, and liver. Their studies revealed profound repression of peroxisome proliferator-activated receptor-gamma (PPARG; <a href="/entry/601487">601487</a>), coactivator-1 alpha and beta (PCG1-alpha, <a href="/entry/604517">604517</a> and PGC1-beta, <a href="/entry/608886">608886</a>), and the downstream network. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction was associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC1-alpha expression or germline deletion of p53 substantially restored PGC network expression, mitochondrial respiration, cardiac function, and gluconeogenesis. <a href="#31" class="mim-tip-reference" title="Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., and 18 others. <strong>Telomere dysfunction induces metabolic and mitochondrial compromise.</strong> Nature 470: 359-365, 2011. Note: Erratum: Nature 475: 254 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307849[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/nature09787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307849">Sahin et al. (2011)</a> demonstrated that telomere dysfunction activates p53 which in turn binds and represses PGC1-alpha and PGC1-beta promoters, thereby forging a direct link between telomere and mitochondrial biology. <a href="#31" class="mim-tip-reference" title="Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., and 18 others. <strong>Telomere dysfunction induces metabolic and mitochondrial compromise.</strong> Nature 470: 359-365, 2011. Note: Erratum: Nature 475: 254 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307849[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/nature09787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307849">Sahin et al. (2011)</a> proposed that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21307849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Schratz, K. E., Flasch, D. A., Atik, C. C., Cosner, Z. L., Blackford, A. L., Yang, W., Gable, D. L., Vellanki, P. J., Xiang, Z., Gaysinskaya, V., Vonderheide, R. H., Rooper, L. M., Zhang, J., Armanios, M. <strong>T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers.</strong> Cancer Cell 41: 807-817, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37037617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37037617</a>] [<a href="https://doi.org/10.1016/j.ccell.2023.03.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37037617">Schratz et al. (2023)</a> found that Terc-null mice developed short telomeres after several generations. These mice showed CD4+ and CD8+ T-cell lymphopenia and impaired tumor surveillance with evidence of T-cell dropout and T-cell exhaustion with aging. The findings suggested that short telomere syndromes may increase the risk for cancers that rely on T-cell competence for their suppression, including squamous cell carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37037617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a large family with autosomal dominant dyskeratosis congenita-1 (DKCA1; <a href="/entry/127550">127550</a>), <a href="#37" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., Dokal, I. <strong>The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.</strong> Nature 413: 432-435, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11574891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11574891</a>] [<a href="https://doi.org/10.1038/35096585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11574891">Vulliamy et al. (2001)</a> identified an 821-bp deletion on chromosome 3q that removes the 3-prime 74 basepairs of TERC. This mutation was identified in all affected family members in the heterozygous state and was not identified in any unaffected family members, nor in a panel of 50 unrelated individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11574891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DOMINANT 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422284;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=rs199422284" 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=rs199422284" 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=RCV000007744" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007744" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007744</a>
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<p>In a large family with autosomal dominant dyskeratosis congenita-1 (DKCA1; <a href="/entry/127550">127550</a>), <a href="#37" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., Dokal, I. <strong>The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.</strong> Nature 413: 432-435, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11574891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11574891</a>] [<a href="https://doi.org/10.1038/35096585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11574891">Vulliamy et al. (2001)</a> identified a C-to-G substitution at nucleotide 408 of the TERC gene. In this family the father had only mild hematologic abnormalities, whereas his children, ages 10 and 12 years, had severe bone marrow failure in association with other somatic abnormalities. This mutation was associated with a wildtype level of transcript, and was not identified in a panel of 50 unrelated individuals tested. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11574891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DOMINANT 1</strong>
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TERC, 107/8GC-AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476393 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476393;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=rs199476393" 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=rs199476393" 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=RCV000007745" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007745" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007745</a>
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</span>
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<span class="mim-text-font">
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<p>In a large family with autosomal dominant dyskeratosis congenita-1 (DKCA1; <a href="/entry/127550">127550</a>), <a href="#37" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., Dokal, I. <strong>The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.</strong> Nature 413: 432-435, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11574891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11574891</a>] [<a href="https://doi.org/10.1038/35096585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11574891">Vulliamy et al. (2001)</a> identified a GC-to-AG substitution at nucleotides 107 to 108 of the TERC gene. This mutation was present in all affected family members and was not identified in unaffected family members; it was also not identified in a panel of 50 unrelated individuals tested. The transcript was present at wildtype levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11574891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0004" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0004 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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TERC, 58G-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> rs113487931 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113487931;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/rs113487931?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=rs113487931" 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=rs113487931" 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=RCV000007747 OR RCV000032580 OR RCV000229649 OR RCV000421480 OR RCV001699177 OR RCV002490336" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007747, RCV000032580, RCV000229649, RCV000421480, RCV001699177, RCV002490336" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007747...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p><a href="#36" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. <strong>Association between aplastic anaemia and mutations in telomerase RNA.</strong> Lancet 359: 2168-2170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12090986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12090986</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12090986">Vulliamy et al. (2002)</a> found a c.58G-A transition in the TERC gene in a 22-year-old man with telomere-related bone marrow failure (PFBMFT2; <a href="/entry/614743">614743</a>), short stature, and phimosis with negative family history; and in 2 unrelated patients, a 5-year-old boy and a 53-year-old woman with nonsevere aplastic anemia and no indications of constitutional involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12090986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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TERC, 72C-G
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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> rs199422265 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422265;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/rs199422265?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=rs199422265" 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=rs199422265" 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=RCV000007748 OR RCV000032581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007748, RCV000032581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007748...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p><a href="#36" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. <strong>Association between aplastic anaemia and mutations in telomerase RNA.</strong> Lancet 359: 2168-2170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12090986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12090986</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12090986">Vulliamy et al. (2002)</a> found a c.72C-G transversion in the TERC gene in a 33-year-old man with telomere-related bone marrow failure (PFBMFT2; <a href="/entry/614743">614743</a>) and severe osteoporosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12090986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<h4>
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<span class="mim-font">
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<strong>.0006 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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</span>
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</h4>
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</div>
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TERC, 4-BP DEL, 110GACT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422270 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422270;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=rs199422270" 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=rs199422270" 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=RCV000007749 OR RCV000032556 OR RCV001214506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007749, RCV000032556, RCV001214506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007749...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 26-year-old man and his sister with telomere-related bone marrow failure (PFBMFT2; <a href="/entry/614743">614743</a>), <a href="#36" class="mim-tip-reference" title="Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. <strong>Association between aplastic anaemia and mutations in telomerase RNA.</strong> Lancet 359: 2168-2170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12090986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12090986</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12090986">Vulliamy et al. (2002)</a> found a 4-bp deletion (c.110-113GACT) in the TERC gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12090986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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, 2</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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TERC, 116C-T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422272 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422272;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=rs199422272" 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=rs199422272" 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=RCV000007750 OR RCV000032559 OR RCV001818142 OR RCV002509148" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007750, RCV000032559, RCV001818142, RCV002509148" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007750...</a>
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<p>In 2 families in which an adult was initially diagnosed with acquired aplastic anemia, <a href="#16" class="mim-tip-reference" title="Fogarty, P. F., Yamaguchi, H., Wiestner, A., Baerlocher, G. M., Sloand, E., Zeng, W. S., Read, E. J., Lansdorp, P. M., Young, N. S. <strong>Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA.</strong> Lancet 362: 1628-1630, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14630445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14630445</a>] [<a href="https://doi.org/10.1016/S0140-6736(03)14797-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14630445">Fogarty et al. (2003)</a> identified heterozygous point mutations in the TERC gene in affected members of both families: a c.116C-T transition in the pseudoknot domain (CR2/CR3) in 1 family, and a c.204C-G transversion (<a href="#0008">602322.0008</a>) in the other. Affected members of both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin (PFBMFT2; <a href="/entry/614743">614743</a>). Neither mutation was found in 194 phenotypically normal individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14630445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422277 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422277;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=rs199422277" 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=rs199422277" 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=RCV000007746 OR RCV000032564" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007746, RCV000032564" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007746...</a>
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<p>In 2 families in which an adult was initially diagnosed with acquired aplastic anemia, <a href="#16" class="mim-tip-reference" title="Fogarty, P. F., Yamaguchi, H., Wiestner, A., Baerlocher, G. M., Sloand, E., Zeng, W. S., Read, E. J., Lansdorp, P. M., Young, N. S. <strong>Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA.</strong> Lancet 362: 1628-1630, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14630445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14630445</a>] [<a href="https://doi.org/10.1016/S0140-6736(03)14797-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14630445">Fogarty et al. (2003)</a> identified heterozygous point mutations in the TERC gene in affected members of both families: a c.116C-T transition (<a href="#0007">602322.0007</a>) in the pseudoknot domain (CR2/CR3) in 1 family, and a c.204C-G transversion in the other. Affected members of both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin (PFBMFT2; <a href="/entry/614743">614743</a>). Neither mutation was found in 194 phenotypically normal individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14630445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Parry, E. M., Alder, J. K., Qi, X., Chen, J. J.-L., Armanios, M. <strong>Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase.</strong> Blood 117: 5607-5611, 2011. Note: Erratum: Blood 127: 1837 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21436073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21436073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21436073[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/10.1182/blood-2010-11-322149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21436073">Parry et al. (2011)</a> identified a heterozygous c.204C-G transversion in the TERC gene in 3 members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure-2. The telomere length in mutation carriers was less than 1% of control, and the mutation was demonstrated to result in compromised telomerase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21436073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 PULMONARY FIBROSIS AND BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422268 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422268;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=rs199422268" 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=rs199422268" 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=RCV000007751 OR RCV000032584" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007751, RCV000032584" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007751...</a>
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<p>In a female nonsmoker with telomere-related pulmonary fibrosis (PFBMFT2; <a href="/entry/614743">614743</a>) who was diagnosed at 60 years of age and who died at age 66 years, <a href="#4" class="mim-tip-reference" title="Armanios, M. Y., Chen, J. J.-L., Cogan, J. D., Alder, J. K., Ingersoll, R. G., Markin, C., Lawson, W. E., Xie, M., Vulto, I., Phillips, J. A., III, Lansdorp, P. M., Greider, C. W., Loyd, J. E. <strong>Telomerase mutations in families with idiopathic pulmonary fibrosis.</strong> New Eng. J. Med. 356: 1317-1326, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17392301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17392301</a>] [<a href="https://doi.org/10.1056/NEJMoa066157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17392301">Armanios et al. (2007)</a> identified heterozygosity for a c.98G-A transition at a highly conserved site in the TERC gene, predicted to impair base pairing in a helix of the essential pseudoknot domain. Reconstitution of telomerase with the mutant 98A allele revealed severe impairment of activity. The mutation was not found in 194 healthy controls. Six family members had died of pulmonary fibrosis, including the proband's mother; 3 died from aplastic anemia, and 1 individual died from acute myeloid leukemia, probably in the setting of aplastic anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17392301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1777959964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1777959964;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=rs1777959964" 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=rs1777959964" 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=RCV000007752" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007752" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007752</a>
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<p>In a patient with telomere-related pulmonary fibrosis (PFBMFT2; <a href="/entry/614743">614743</a>), <a href="#2" class="mim-tip-reference" title="Alder, J. K., Chen, J. J.-L., Lancaster, L., Danoff, S., Su, S., Cogan, J. D., Vulto, I., Xie, M., Qi, X., Tuder, R. M., Phillips, J. A., III, Lansdorp, P. M., Loyd, J. E., Armanios, M. Y. <strong>Short telomeres are a risk factor for idiopathic pulmonary fibrosis.</strong> Proc. Nat. Acad. Sci. 105: 13051-13056, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18753630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18753630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18753630[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0804280105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18753630">Alder et al. (2008)</a> identified heterozygosity for a 325G-T transversion in the TERC gene, predicted to disrupt the conserved P5 helix. Younger asymptomatic sibs of the proband also carried the mutation, which was associated with short telomeres and led to a loss of activity as quantitated by the direct telomerase activity assay. The mutation was not found in 194 healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18753630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422263;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=rs199422263" 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=rs199422263" 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=RCV000023192 OR RCV003480035" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023192, RCV003480035" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023192...</a>
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<p>In 7 members of a Dutch family with autosomal dominant dyskeratosis congenita (DKCA1; <a href="/entry/127550">127550</a>), <a href="#21" class="mim-tip-reference" title="Jongmans, M. C. J., Verwiel, E. T. P., Heijdra, Y., Vulliamy, T., Kamping, E. J., Hehir-Kwa, J. Y., Bongers, E. M. H. F., Pfundt, R., van Emst, L., van Leeuwen, F. N., van Gassen, K. L. I., Geurts van Kessel, A., Dokal, I., Hoogerbrugge, N., Ligtenberg, M. J. L., Kuiper, R. P. <strong>Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita.</strong> Am. J. Hum. Genet. 90: 426-433, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22341970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22341970</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22341970[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.01.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22341970">Jongmans et al. (2012)</a> identified a heterozygous 4-bp deletion (c.54_57del) in the TERC gene. The proband was a 26-year-old man with multiple features of the disorder, including dystrophic nails, reticular pigmentation of the neck and chest, gray lock of hair, aplastic anemia, pulmonary fibrosis, liver disease, and avascular necrosis of the hip. The family history was positive for pulmonary fibrosis, cirrhosis, and aplastic anemia. Although the mutation segregated with the disease, the mutation load was decreased in blood of the proband's father and the father's brother, both of whom had disease limited to pulmonary fibrosis. The findings suggested somatic reversion of the mutated allele to a normal state. SNP analysis of the blood from the father and uncle showed that both had an acquired uniparental disomy of chromosome 3q, including the TERC gene. Detailed blood analysis of 1 of the brothers showed 2 different mosaic reversion patterns in B cells, granulocytes, and monocytes. T cells showed heterozygous levels of the mutant allele, consistent with the longer lifespan of these cells. Thus, mitotic recombination explained the reversion and phenotypic variability in the brothers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22341970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0012 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422274 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422274;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=rs199422274" 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=rs199422274" 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=RCV000032561 OR RCV001610304" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032561, RCV001610304" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032561...</a>
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<p>In 3 members of a family spanning 3 generations with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-2 (PFBMFT2; <a href="/entry/614743">614743</a>), <a href="#29" class="mim-tip-reference" title="Parry, E. M., Alder, J. K., Qi, X., Chen, J. J.-L., Armanios, M. <strong>Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase.</strong> Blood 117: 5607-5611, 2011. Note: Erratum: Blood 127: 1837 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21436073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21436073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21436073[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/10.1182/blood-2010-11-322149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21436073">Parry et al. (2011)</a> identified a heterozygous c.143G-A transition in the TERC gene. One patient had pulmonary fibrosis, 1 had pulmonary fibrosis and liver disease, and 1 had bone marrow failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21436073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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TERC, 212C-G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108183105 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108183105;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=rs2108183105" 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=rs2108183105" 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=RCV000030634" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030634" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030634</a>
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<p>In a father and son with telomere-related bone marrow failure (PFBMFT2; <a href="/entry/614743">614743</a>), <a href="#22" class="mim-tip-reference" title="Kirwan, M., Vulliamy, T., Marrone, A., Walne, A. J., Beswick, R., Hillmen, B., Kelly, R., Stewart, A., Bowen, D., Schonland, S. O., Whittle, A. M., McVerry, A., Gilleece, M., Dokal, I. <strong>Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia.</strong> Hum. Mutat. 30: 1567-1573, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19760749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19760749</a>] [<a href="https://doi.org/10.1002/humu.21115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19760749">Kirwan et al. (2009)</a> identified a heterozygous c.212C-G transversion in the TERC gene. The son had severe aplastic anemia, whereas the father presented with myelodysplastic syndrome at age 45 years. In vitro studies showed less than 1% telomerase activity, and telomeres in the father were very short. The findings suggested that constitutional TERC mutations are associated with the development of myelodysplastic syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19760749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Agarwal2010" class="mim-anchor"></a>
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Agarwal, S., Loh, Y.-H., McLoughlin, E. M., Huang, J., Park, I-H., Miller, J. D., Huo, H., Okuka, M., dos Reis, R. M., Loewer, S., Hg, H.-H., Keefe, D. L., Goldman, F. D., Klingelhutz, A. J., Liu, L., Daley, G. Q.
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<strong>Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.</strong>
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Nature 464: 292-296, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20164838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20164838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20164838[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=20164838" 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/nature08792" target="_blank">Full Text</a>]
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<a id="Alder2008" class="mim-anchor"></a>
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Alder, J. K., Chen, J. J.-L., Lancaster, L., Danoff, S., Su, S., Cogan, J. D., Vulto, I., Xie, M., Qi, X., Tuder, R. M., Phillips, J. A., III, Lansdorp, P. M., Loyd, J. E., Armanios, M. Y.
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<strong>Short telomeres are a risk factor for idiopathic pulmonary fibrosis.</strong>
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Proc. Nat. Acad. Sci. 105: 13051-13056, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18753630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18753630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18753630[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=18753630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0804280105" target="_blank">Full Text</a>]
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<a id="Armanios2009" class="mim-anchor"></a>
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Armanios, M., Alder, J. K., Parry, E. M., Karim, B., Strong, M. A., Greider, C. W.
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<strong>Short telomeres are sufficient to cause the degenerative defects associated with aging.</strong>
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Am. J. Hum. Genet. 85: 823-832, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19944403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19944403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19944403[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=19944403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2009.10.028" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Armanios2007" class="mim-anchor"></a>
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Armanios, M. Y., Chen, J. J.-L., Cogan, J. D., Alder, J. K., Ingersoll, R. G., Markin, C., Lawson, W. E., Xie, M., Vulto, I., Phillips, J. A., III, Lansdorp, P. M., Greider, C. W., Loyd, J. E.
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<strong>Telomerase mutations in families with idiopathic pulmonary fibrosis.</strong>
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New Eng. J. Med. 356: 1317-1326, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17392301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17392301</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17392301" 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/10.1056/NEJMoa066157" target="_blank">Full Text</a>]
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<a id="Artandi2000" class="mim-anchor"></a>
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Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., DePinho, R. A.
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<strong>Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.</strong>
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Nature 406: 641-645, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10949306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10949306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10949306" 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/10.1038/35020592" target="_blank">Full Text</a>]
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<a id="Baird2003" class="mim-anchor"></a>
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Baird, D. M., Rowson, J., Wynford-Thomas, D., Kipling, D.
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<strong>Extensive allelic variation and ultrashort telomeres in senescent human cells.</strong>
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Nature Genet. 33: 203-207, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539050</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539050" 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/ng1084" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Ball1998" class="mim-anchor"></a>
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<div class="">
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Ball, S. E., Gibson, F. M., Rizzo, S., Tooze, J. A., Marsh, J. C. W., Gordon-Smith, E. C.
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<strong>Progressive telomere shortening in aplastic anemia.</strong>
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Blood 91: 3582-3592, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9572992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9572992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9572992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Begus-Nahrmann2009" class="mim-anchor"></a>
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Begus-Nahrmann, Y., Lechel, A., Obenauf, A. C., Nalapareddy, K., Peit, E., Hoffmann, E., Schlaudraff, F., Liss, B., Schirmacher, P., Kestler, H., Danenberg, E., Barker, N., Clevers, H., Speicher, M. R., Rudolph, K. L.
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<strong>p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice.</strong>
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Nature Genet. 41: 1138-1143, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718028</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19718028" 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.426" target="_blank">Full Text</a>]
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<a id="Blasco1997" class="mim-anchor"></a>
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Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., Greider, C. W.
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<strong>Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.</strong>
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Cell 91: 25-34, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9335332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9335332</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9335332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(01)80006-4" target="_blank">Full Text</a>]
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<a id="Box2008" class="mim-anchor"></a>
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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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[<a href="https://doi.org/10.1016/j.ccell.2023.03.005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(02)09087-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1346" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/79232" target="_blank">Full Text</a>]
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<a id="Wong2003" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/nature01385" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 05/17/2023
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Ada Hamosh - updated : 02/08/2016<br>Cassandra L. Kniffin - updated : 8/2/2012<br>Cassandra L. Kniffin - updated : 3/27/2012<br>Ada Hamosh - updated : 6/29/2011<br>Ada Hamosh - updated : 6/18/2010<br>Ada Hamosh - updated : 4/22/2010<br>Ada Hamosh - updated : 3/18/2010<br>Ada Hamosh - updated : 1/12/2010<br>Marla J. F. O'Neill - updated : 3/18/2009<br>Ada Hamosh - updated : 3/10/2009<br>Ada Hamosh - updated : 2/18/2009<br>Patricia A. Hartz - updated : 8/25/2008<br>Patricia A. Hartz - updated : 10/18/2007<br>Ada Hamosh - updated : 4/12/2007<br>Patricia A. Hartz - updated : 3/2/2007<br>Natalie E. Krasikov - updated : 8/10/2004<br>Victor A. McKusick - updated : 4/26/2004<br>Marla J. F. O'Neill - updated : 2/2/2004<br>Victor A. McKusick - updated : 2/20/2003<br>Victor A. McKusick - updated : 2/11/2003<br>Ada Hamosh - updated : 2/3/2003<br>Victor A. McKusick - updated : 2/3/2003<br>Stylianos E. Antonarakis - updated : 10/30/2001<br>Ada Hamosh - updated : 9/26/2001<br>Stylianos E. Antonarakis - updated : 9/8/2000<br>Victor A. McKusick - updated : 8/28/2000<br>Ada Hamosh - updated : 12/1/1999<br>Stylianos E. Antonarakis - updated : 8/31/1999<br>Stylianos E. Antonarakis - updated : 3/25/1999<br>Victor A. McKusick - updated : 5/27/1998<br>Victor A. McKusick - updated : 4/22/1998<br>Victor A. McKusick - updated : 4/7/1998
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Rebekah S. Rasooly : 2/9/1998
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alopez : 05/25/2023
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ckniffin : 05/17/2023<br>alopez : 05/08/2023<br>alopez : 11/27/2019<br>ckniffin : 11/27/2019<br>carol : 03/20/2018<br>carol : 03/20/2018<br>carol : 08/23/2017<br>alopez : 02/08/2016<br>carol : 5/12/2015<br>carol : 8/6/2012<br>ckniffin : 8/2/2012<br>carol : 4/2/2012<br>ckniffin : 3/27/2012<br>alopez : 8/25/2011<br>alopez : 7/5/2011<br>alopez : 7/5/2011<br>terry : 6/29/2011<br>carol : 5/26/2011<br>ckniffin : 5/25/2011<br>alopez : 6/29/2010<br>terry : 6/18/2010<br>alopez : 4/26/2010<br>terry : 4/22/2010<br>alopez : 3/18/2010<br>wwang : 1/21/2010<br>wwang : 1/21/2010<br>alopez : 1/14/2010<br>terry : 1/12/2010<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>wwang : 3/23/2009<br>terry : 3/18/2009<br>alopez : 3/13/2009<br>terry : 3/10/2009<br>alopez : 2/20/2009<br>terry : 2/18/2009<br>terry : 9/10/2008<br>mgross : 8/26/2008<br>mgross : 8/26/2008<br>terry : 8/25/2008<br>mgross : 10/23/2007<br>terry : 10/18/2007<br>wwang : 7/9/2007<br>ckniffin : 6/12/2007<br>alopez : 4/13/2007<br>terry : 4/12/2007<br>mgross : 3/9/2007<br>terry : 3/2/2007<br>mgross : 11/17/2006<br>carol : 8/16/2005<br>carol : 1/5/2005<br>carol : 1/4/2005<br>carol : 8/10/2004<br>terry : 8/10/2004<br>terry : 6/18/2004<br>alopez : 5/3/2004<br>alopez : 4/27/2004<br>terry : 4/26/2004<br>joanna : 3/17/2004<br>carol : 2/2/2004<br>tkritzer : 5/7/2003<br>alopez : 2/28/2003<br>tkritzer : 2/20/2003<br>mgross : 2/14/2003<br>terry : 2/11/2003<br>alopez : 2/4/2003<br>alopez : 2/4/2003<br>terry : 2/3/2003<br>terry : 2/3/2003<br>carol : 2/6/2002<br>mgross : 10/30/2001<br>alopez : 9/26/2001<br>terry : 9/26/2001<br>mgross : 9/8/2000<br>alopez : 8/29/2000<br>terry : 8/28/2000<br>alopez : 12/1/1999<br>mgross : 8/31/1999<br>mgross : 3/31/1999<br>mgross : 3/26/1999<br>terry : 3/25/1999<br>alopez : 6/1/1998<br>terry : 5/27/1998<br>alopez : 4/22/1998<br>terry : 4/7/1998<br>alopez : 4/2/1998<br>alopez : 2/9/1998
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<strong>*</strong> 602322
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TELOMERASE RNA COMPONENT; TERC
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TELOMERASE RNA CANDIDATE 3; TRC3<br />
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TR
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TERC</em></strong>
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Cytogenetic location: 3q26.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:169,764,610-169,765,060 </span>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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3q26.2
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Dyskeratosis congenita, autosomal dominant 1
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<span class="mim-font">
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127550
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Autosomal dominant
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3
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2
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<span class="mim-font">
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614743
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Eukaryotic chromosomes are capped with repetitive telomere sequences that protect the ends from damage and rearrangements. Telomere repeats are synthesized by telomerase, an enzyme that has both a catalytic (TERT; 187270) and an RNA component. The RNA component acts as a template for the addition of telomeric repeat sequences (Feng et al., 1995). </p>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Feng et al. (1995) cloned the 451-nucleotide gene for the telomerase RNA component, which they designated TRC3. TRC3 copurified with telomerase. TRC3 was highly expressed in the germline and in tumor cell lines, which had high telomerase activity, and at lower levels in kidney, prostate, and liver, which had no detectable telomerase activity. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Soder et al. (1997) mapped the mouse Terc gene to chromosome 3 and, based on syntenic homology with human chromosomes, suggested that the human TERC gene is located on 3q21-q28. </p>
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<strong>Gene Function</strong>
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<p>Feng et al. (1995) found that HeLa cells transfected with antisense TRC3 lost telomeric DNA and began to die after 23 to 26 divisions, showing that telomerase is critical for the long-term proliferation of tumor cells. </p><p>Inhibition or activation of the reverse transcriptase telomerase can profoundly affect the proliferative capacity of normal cells and cancers. Mitchell and Collins (2000) elucidated structural requirements for function of the essential RNA component of human telomerase, TR. Two motifs within the independently stable H/ACA domain of TR are required for accumulation of the mature RNA in vivo. However, these motifs can be substituted by a heterologous H/ACA family RNA. Two additional TR elements are required both in vivo and in vitro for telomerase catalytic activity. Surprisingly, these elements independently bind the telomerase reverse transcriptase. The results established fundamental differences between vertebrate and ciliate telomerase ribonucleoprotein architectures. </p><p>Mitchell et al. (1999) demonstrated that dyskerin (300126) is associated not only with H/ACA small nucleolar RNAs but also with human telomerase RNA, which contains an H/ACA RNA motif. They found that primary fibroblasts and lymphoblasts from dyskeratosis congenita (DKC; 305000)-affected males were not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function. However, DKC cells had a lower level of telomerase RNA, produced lower levels of telomerase activity than matched normal cells, and had shorter telomeres. Mitchell et al. (1999) concluded that the pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood. </p><p>De Lange and Jacks (1999) provided a comprehensive review of the status of knowledge concerning the biologic importance of TERC. </p><p>Okuda et al. (2002) found no evidence for gender effect on telomere length at birth and suggested that the longer length of telomeres in women is due to a slower rate of telomere shortening. </p><p>Cohen et al. (2007) purified human telomerase 10(8)-fold, with the final elution dependent on the enzyme's ability to catalyze nucleotide addition onto a DNA oligonucleotide of telomeric sequence, thereby providing specificity for catalytically active telomerase. Mass spectrometric sequencing of the protein components and molecular size determination indicated an enzyme composition of 2 molecules each of telomerase reverse transcriptase (TERT; 187270) and TERC. </p><p>Cristofari et al. (2007) stated that telomerase accumulates in Cajal bodies (CBs) and that this localization relies on a CAB box motif (UGAG) within the loop of a stem-loop structure of TERC. They found that mutations of the CAB box of human TERC that impaired accumulation of telomerase in CBs did not affect telomerase catalytic activity in vivo, but they decreased association of telomerase with telomeres and impaired telomere extension in human cells. Cristofari et al. (2007) concluded that localization of telomerase within CBs is required to maintain telomere length. </p><p>Box et al. (2008) showed that in Schizosaccharomyces pombe telomerase RNA transcripts must be processed to generate functional telomerase. Characterization of the maturation pathway uncovered an unexpected role for the spliceosome, which normally catalyzes splicing of pre-messenger RNA. The first spliceosomal cleavage reaction generates the mature 3-prime end of telomerase RNA (TER1, the functional RNA encoded by the ter1+ gene), releasing the active form of the RNA without exon ligation. Blocking the first step or permitting completion of splicing generates inactive forms of TER1 and causes progressive telomere shortening. Box et al. (2008) established that 3-prime end processing of TER1 is critical for telomerase function and described a theretofore unknown mechanism for RNA maturation that uses the ability of the spliceosome to mediate site-specific cleavage. </p><p>Venteicher et al. (2009) found that TCAB1 (612661) associates with TERT, established telomerase components dyskerin (300126) and TERC, and small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevented TERC from associating with Cajal bodies, disrupted telomerase-telomere association, and abrogated telomere synthesis in telomerase. Thus, Venteicher et al. (2009) concluded that TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells. </p><p>A cardinal feature of induced pluripotent stem cells (iPS) is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene TERT. Agarwal et al. (2010) investigated whether defects in telomerase function would limit derivation maintenance of iPS cells from patients with dyskeratosis congenita (DKC; see 127550). The authors showed that reprogrammed dendritic congenita cells overcome a critical limitation in TERC levels to restore telomere maintenance and self-renewal. Agarwal et al. (2010) discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DKC, transcriptional silencing accompanies a 3-prime deletion at the TERC locus. Agarwal et al. (2010) concluded that their results demonstrated that reprogramming restores telomere elongation in DKC cells despite genetic lesions affecting telomerase, and showed that strategies to increase TERC expression may be therapeutically beneficial in DKC. </p><p>Using somatic cells and induced pluripotent stem cells (iPSCs) from patients with dyskeratosis congenita with PARN (604212) mutations, Moon et al. (2015) demonstrated that PARN is required for the 3-prime-end maturation of TERC. 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>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Autosomal Dominant Dyskeratosis Congenita 1</em></strong></p><p>
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Vulliamy et al. (2001) identified 3 different mutations in TERC in 3 families segregating autosomal dominant dyskeratosis congenita-1 (DKCA1; 127550). The first mutation (602322.0001) resulted in an 821-bp deletion including the 74 3-prime basepairs of the coding region. The deleted region is flanked by a 4-bp direct repeat, AGGA. Lymphocyte cell lines derived from affected individuals in this family were examined by Northern blot analysis. No difference was found between cell lines from affected and unaffected individuals; however, RT-PCR using a mutant-specific 3-prime primer abutting the point of the deletion showed that the mutant transcript is barely detectable. Telomere length in affected family members was significantly shorter than in normal patients, even in young children with manifestation of disease. The second mutation was a single-basepair substitution at nucleotide 408 (602322.0002). This mutation did not affect transcript levels, but is predicted to destabilize the stem structure in the CR7 domain. A third family had a 2-bp substitution at nucleotides 107 to 108 (602322.0003). This mutation also did not affect transcript levels but appears to destabilize a hairpin stem region in the pseudoknot region of the proposed secondary structure of TERC. This region is essential for telomerase activity and seems to be involved in interaction with telomere reverse transcriptase (TERT; 187270). </p><p>Theimer et al. (2003) demonstrated that mutations in the TERC gene that result in autosomal dominant dyskeratosis congenita cause changes in the structural equilibrium of RNA polymerase. They reported structural and thermodynamic studies of wildtype and mutant human telomerase subdomains that provided 3D structural insight into the molecular basis of the disease. The work revealed the presence of a phylogenetically conserved hairpin in equilibrium with a pseudoknot in the telomerase pseudoknot domain, which is stabilized by a unique uridine helix. Theimer et al. (2003) proposed that interconversion between the hairpin and pseudoknot conformations is functionally important, and that pseudoknot mutations in dyskeratosis congenita affect this interconversion. </p><p>Vulliamy et al. (2004) demonstrated that anticipation occurs in autosomal dominant dyskeratosis congenita and that the molecular basis resides in progressive telomere shortening in successive generations. In 8 families, the disease became more severe in succeeding generations. Of affected parents, 7 of 12 were asymptomatic, ranging in age from 36 to 61 years. In these cases, dyskeratosis congenita was diagnosed only by the identification of a TERC mutation; subtle signs of the disease were often detected subsequently. For the 5 remaining affected parents, the median age at which disease features were first identified was 37 years. Of the affected children, only 5 of 15 remained asymptomatic; they were aged 3, 7, 11, 14, and 20 years and were diagnosed only through mutation analysis. For the remaining 10 affected children, symptoms presented at a median age of 14.5 years. Vulliamy et al. (2004) also observed a number of individuals who had a bimodal distribution of telomere length. A bimodal distribution had previously been observed in human fibroblast cell lines where the short and long telomeres were linked to maternal and paternal alleles. The difference in telomere length between the 2 alleles seemed to be maintained from the zygote throughout development (Baird et al., 2003). Thus, another mechanism was added to the phenomenon of disease anticipation. The only convincing mechanism theretofore described involved expansion of triplet repeats as observed in several neurodegenerative disorders. There are clear analogies here with Terc knockout mice: parental mice have very long telomeres, and in the first generation, Terc -/- mice are asymptomatic. Features of telomere shortening, which overlap the clinical features seen in dyskeratosis congenita, develop only in the fourth generation. By the sixth generation, these mice become infertile. </p><p>Goldman et al. (2005) studied telomere dynamics over 3 generations in a 32-member extended family with autosomal dominant dyskeratosis congenita due to TERC gene deletion. They found that in gene deletion carriers, paternal and maternal telomeres were similarly short and similar in length to those of the affected parent. In children of affected parents who had normal TERC genes, parental telomeres were again similar in length, but 2 generations appeared to be necessary to fully restore normal telomere length. Goldman et al. (2005) concluded that these results were consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting, this preference leads to the accelerated shortening of longer telomeres. </p><p>Jongmans et al. (2012) observed somatic reversion of the mutant TERC allele in blood cells of 2 affected members of a family with variable manifestations of DKCA1 due to a heterozygous germline TERC mutation (602322.0011). In both cases, the reversion occurred by acquired uniparental disomy of chromosome 3q, including TERC, during mitotic recombination. Four additional cases of a mosaic-reversion pattern in blood cells were found among a cohort of 17 patients with germline TERC mutations. None of the patients with somatic mosaic reversion had bone marrow failure, and all had a small deletion in the TERC gene. The findings indicated that revertant somatic mosaicism is a recurrent event in DKCA1, which has important implications for diagnostic testing, often performed on blood cells, and may help explain the variable phenotype of the disorder. </p><p><strong><em>Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome 2</em></strong></p><p>
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|
Bone marrow failure in X-linked dyskeratosis congenita is caused by mutations in the nucleolar protein dyskerin. This protein binds to a particular class of small nucleolar RNAs called H/ACA as well as to telomerase RNA. As discussed above, the very rare autosomal dominant form of dyskeratosis congenita is caused by mutations in the RNA component of telomerase, encoded by the TERC gene, and such patients consequently have very short telomeres (Vulliamy et al., 2001). Patients with idiopathic aplastic anemia and bone marrow failure (see PFBMFT2, 614743) also have shorter telomeres than normal controls (Ball et al., 1998). This prompted Vulliamy et al. (2002) to perform mutation screens of the TERC gene in patients with aplastic anemia. They identified TERC mutations in 2 of 17 patients with idiopathic aplastic anemia, in 3 of 27 patients with constitutional aplastic anemia, and in none of 214 normal controls. Furthermore, patients with TERC mutations had significantly shorter telomeres than age-matched controls. These data indicated that in a subset of patients with aplastic anemia, the disorder may be associated with a genetic lesion in the telomere maintenance pathway. Mutations were heterozygous in each case. The c.58G-A mutation (602322.0004) was found in 3 of the patients, 2 of whom were categorized as having idiopathic aplastic anemia and 1 as having constitutional aplastic anemia (associated with short stature and phimosis). The age at first clinical presentation in these 3 patients varied from 5 to 53 years. This variability in the severity and age of onset in patients with the same mutation highlighted the role of other genetic or environmental factors in the clinical phenotype. Vulliamy et al. (2002) observed that in X-linked dyskeratosis congenita, which is also characterized by aplastic anemia, the recurrent mutation c.1058C-T (300126.0006) is associated with a wide variation in the age at onset of aplastic anemia from 1 to 22 years. The constitutional nature of aplastic anemia can sometimes be overlooked. In the patient of Vulliamy et al. (2002) with the c.72C-G mutation (602322.0005), the presence of pronounced osteoporosis, discovered because of a bone fracture, led to the categorization of constitutional rather than idiopathic disease. Similarly, another patient with a 4-bp deletion in TERC (602322.0006) had aplastic anemia alone; he would have been classified as idiopathic if it were not for his sister who also had aplastic anemia. </p><p>In 2 families in which an adult was initially diagnosed with acquired aplastic anemia, Fogarty et al. (2003) detected novel point mutations in the TERC gene in affected members of both families: a heterozygous c.116C-T transition (602322.0007) in 1 family, and a heterozygous c.204C-G transversion (602322.0008) in the other. Affected members of both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin. </p><p>Armanios et al. (2007) screened 73 probands with familial idiopathic pulmonary fibrosis for mutations in the TERT or TERC genes and identified 5 mutations in TERT (see, e.g., 187270.0010) and 1 in TERC (602322.0009) in 6 probands, respectively. Average telomere length was significantly less in probands and asymptomatic mutation carriers than in relatives who did not carry the mutation (p = 0.006), suggesting that asymptomatic carriers may also be at risk for the disease. </p><p>Alder et al. (2008) screened 100 consecutive patients with sporadic idiopathic interstitial pneumonia, the majority of whom had been diagnosed with idiopathic pulmonary fibrosis, for mutations in the TERT and TERC genes and identified a mutation in 1 patient (602322.0010) that was associated with short telomeres, led to a loss of activity, and was not found in 194 healthy controls. </p><p><strong><em>Telomerase RNA Pseudoknot Domain</em></strong></p><p>
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Mutations causing autosomal dominant dyskeratosis congenita and aplastic anemia include base changes in a highly conserved putative telomerase RNA pseudoknot. Comolli et al. (2002) described functional, structural, and energetic properties of this structure. They demonstrated that the pseudoknot domain exists in 2 alternative states of nearly equal stability in solution: a structured P2b loop domain and the pseudoknot formed by its pairing with P3. They showed that a 2-base mutation, 107GC-108AG (602322.0003), in 1 gene copy in a family with dyskeratosis congenita abrogated telomerase activity. This mutation hyperstabilizes the P2b intraloop structure, blocking pseudoknot formation. Conversely, when the P3 pseudoknot pairing is hyperstabilized by deleting a conserved bulge in P3, telomerase activity also decreases. Comolli et al. (2002) proposed that the P2b/P3 pseudoknot domain acts as a molecular switch, and interconversion between its 2 states is important for telomerase function. Phylogenetic covariation in the P2b and P3 sequences of 35 species provided a compelling set of 'natural' compensatory basepairing changes supporting the existence of the crucial molecular switch. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between mean leukocyte telomere length and genetic variation near the TERC locus, see 609113.</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Lee et al. (1998) investigated the role of the enzyme telomerase in highly proliferative organs in successive generations of mice lacking telomerase RNA. Late-generation animals exhibited defective spermatogenesis, with increased programmed cell death (apoptosis) and decreased proliferation in the testis. Proliferative capacity of hematopoietic cells in the bone marrow and spleen was also compromised. These progressively adverse effects coincided with substantial erosion of telomeres and fusion and loss of chromosomes. These findings indicated an essential role for telomerase, and hence telomeres, in the maintenance of genomic integrity and in the long-term viability of high-renewal organ systems. </p><p>To examine the role of telomerase in normal and neoplastic growth, Blasco et al. (1997) deleted the telomerase RNA component from the mouse germline. Terc -/- mice lacked detectable telomerase activity yet were viable for the 6 generations analyzed. Telomerase-deficient cells could be immortalized in culture and transformed by viral oncogenes, and generated tumors in nude mice following transformation. Telomeres were shown to shorten at a rate of 4.8 +/- 2.4 kb per Terc -/- generation. Cells from the fourth Terc -/- generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions. These results indicated that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice. </p><p>To examine the role of telomerase in telomere maintenance and cellular viability, Niida et al. (1998) established Terc-deficient embryonic stem (ES) cells. It had been known that telomerase activity is absent in cells from Terc knockout mice. Although telomere shortening had been observed in the Terc-deficient cells from first to sixth generation animals, whether telomerase-dependent telomere maintenance was essential for cellular viability remained to be elucidated. Niida et al. (1998) examined Terc-deficient ES cells under long-term culture conditions. During their continual telomere shortening, the growth rate of Terc-deficient ES cells was gradually reduced after more than 300 divisions. An impaired growth rate was maintained to approximately 450 divisions, and then cell growth virtually stopped. </p><p>Rudolph et al. (1999) studied a variety of physiologic processes in an aging cohort of Terc -/- mice. Loss of telomere function did not elicit a full spectrum of classic pathophysiologic symptoms of aging. Age-dependent telomere shortening and accompanying genetic instability were, however, associated with shortened life span, as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, the authors found an increased incidence of spontaneous malignancies. These findings demonstrated a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism. </p><p>Artandi et al. (2000) monitored the cancer phenotype and cytogenetics of large cohorts of telomerase-deficient p53 (191170) mutant mice. Mice lacking the RNA component of telomerase (mTERC) exhibit progressive telomere shortening and ultimately chromosomal instability (end-to-end fusions) as a function of age and of successive generational matings. In generation 1 and 2 mTERC -/- p53 -/- mice that lacked telomerase but retained normal telomere function, median tumor incidence was similar to that of mTERC +/+ p53 -/- and mTERC +/- p53 -/- controls. In contrast, in later generations the progressive decline in telomere function correlated with decreasing tumor latency. Similarly, in p53 +/- cohorts, median tumor latency decreased progressively as telomeres became short and dysfunctional. Telomere attrition in aging telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex nonreciprocal translocations - a classic cytogenetic feature of human carcinomas. Artandi et al. (2000) concluded that their data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers. </p><p>Wong et al. (2000) used the telomerase-deficient mouse, null for the telomerase RNA gene, Terc, to assess the role of telomerase and telomere function in the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernible impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc -/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks, and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. </p><p>Inhibition of telomerase has been proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumor cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumor growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumor therapy, as its inhibition is unlikely to have toxic effects. Gonzalez-Suarez et al. (2000) showed that late-generation Terc -/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumor development in multistage skin carcinogenesis. </p><p>To investigate the processes that trigger cellular responses to telomere dysfunction, Hemann et al. (2001) crossed Tr -/- generation-6 mice that had short telomeres with mice heterozygous for telomerase (Tr +/-) that had long telomeres. The phenotype of the telomerase null offspring was similar to that of the late-generation parent, although only half of the chromosomes were short. Spectral karyotyping analysis revealed that loss of telomere function occurred preferentially on chromosomes with critically short telomeres. These data indicated that it is not the average but rather the shortest telomeres that constitute telomere dysfunction and limit cellular survival in the absence of telomerase. </p><p>Wong et al. (2003) examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and Terc. These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multiorgan system compromise, accelerated aging, and premature death. Wong et al. (2003) showed that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of ataxia-telangiectasia (208900) pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves. </p><p>Goldman et al. (2005) noted that there are important differences in telomere maintenance between mouse and human. Compared with humans, laboratory mice have long telomeres. In addition, telomerase is constitutively active in most murine tissues, whereas in humans telomerase activity is greatly diminished in most somatic cells with the exception of stem cells, their immediate progeny, and activated lymphocytes and monocytes. </p><p>Hockemeyer et al. (2008) noted that mice lacking components of telomerase fail to show phenotypes typical of DC. They developed a mouse model in which key characteristics of DC were induced by enhanced telomere degradation. Mice lacking the shelterin component Pot1b (606478) (Pot1b -/-) and also deficient in Terc (Terc +/-) developed progressive bone marrow failure, hyperpigmentation, and nail abnormalities. Bone marrow failure was fatal between 4 and 5 months of age in Pot1b -/- Terc +/- mice. </p><p>Begus-Nahrmann et al. (2009) analyzed the functional consequences of conditional deletion of p53 (191170) in late-generation telomerase knockout mice (Terc-null). Intestinal deletion of p53 shortened the life span of telomere-dysfunctional mice without inducing tumor formation. In contrast to deletion of p21 (116899), which elongates life span of telomere-dysfunctional mice, the deletion of p53 impaired the depletion of chromosomal-instable intestinal stem cells in aging telomere-dysfunctional mice. These instable stem cells contributed to epithelial regeneration leading to an accumulation of chromosomal instability, increased apoptosis, altered epithelial cell differentiation, and premature intestinal failure. Begus-Nahrmann et al. (2009) concluded that their results provided the first experimental evidence for an organ system in which p53-dependent mechanisms prevent tissue destruction in response to telomere dysfunction by depleting genetically instable stem cells. </p><p>Armanios et al. (2009) generated wildtype mice with short telomeres. In these mice, Armanios et al. (2009) identified hematopoietic and immune defects that resembled those present in patients with dyskeratosis congenita (see 305000). Patients with dyskeratosis congenita have a premature aging syndrome that can be caused by mutations in the RNA or catalytic component of telomerase (TERC or TERT, 187270). When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wildtype mice with short telomeres still displayed degenerative defects. Armanios et al. (2009) concluded that their findings implicated telomere length as a unique heritable trait and demonstrated that short telomeres are sufficient to mediate the degenerative defects of aging. </p><p>Sahin et al. (2011) used transcriptomic network analyses in mice null for either Tert or Terc, which exhibit telomere dysfunction, to identify common mechanisms operative in hematopoietic stem cells, heart, and liver. Their studies revealed profound repression of peroxisome proliferator-activated receptor-gamma (PPARG; 601487), coactivator-1 alpha and beta (PCG1-alpha, 604517 and PGC1-beta, 608886), and the downstream network. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction was associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC1-alpha expression or germline deletion of p53 substantially restored PGC network expression, mitochondrial respiration, cardiac function, and gluconeogenesis. Sahin et al. (2011) demonstrated that telomere dysfunction activates p53 which in turn binds and represses PGC1-alpha and PGC1-beta promoters, thereby forging a direct link between telomere and mitochondrial biology. Sahin et al. (2011) proposed that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction. </p><p>Schratz et al. (2023) found that Terc-null mice developed short telomeres after several generations. These mice showed CD4+ and CD8+ T-cell lymphopenia and impaired tumor surveillance with evidence of T-cell dropout and T-cell exhaustion with aging. The findings suggested that short telomere syndromes may increase the risk for cancers that rely on T-cell competence for their suppression, including squamous cell carcinoma. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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TERC, 821-BP DEL
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<br />
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SNP: rs1553915517,
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ClinVar: RCV000007743
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</span>
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<span class="mim-text-font">
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<p>In a large family with autosomal dominant dyskeratosis congenita-1 (DKCA1; 127550), Vulliamy et al. (2001) identified an 821-bp deletion on chromosome 3q that removes the 3-prime 74 basepairs of TERC. This mutation was identified in all affected family members in the heterozygous state and was not identified in any unaffected family members, nor in a panel of 50 unrelated individuals. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 1</strong>
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</span>
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<div>
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<span class="mim-text-font">
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TERC, 408C-G
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<br />
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SNP: rs199422284,
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ClinVar: RCV000007744
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<div>
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<span class="mim-text-font">
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<p>In a large family with autosomal dominant dyskeratosis congenita-1 (DKCA1; 127550), Vulliamy et al. (2001) identified a C-to-G substitution at nucleotide 408 of the TERC gene. In this family the father had only mild hematologic abnormalities, whereas his children, ages 10 and 12 years, had severe bone marrow failure in association with other somatic abnormalities. This mutation was associated with a wildtype level of transcript, and was not identified in a panel of 50 unrelated individuals tested. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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TERC, 107/8GC-AG
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<br />
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SNP: rs199476393,
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ClinVar: RCV000007745
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<span class="mim-text-font">
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<p>In a large family with autosomal dominant dyskeratosis congenita-1 (DKCA1; 127550), Vulliamy et al. (2001) identified a GC-to-AG substitution at nucleotides 107 to 108 of the TERC gene. This mutation was present in all affected family members and was not identified in unaffected family members; it was also not identified in a panel of 50 unrelated individuals tested. The transcript was present at wildtype levels. </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TERC, 58G-A
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<br />
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SNP: rs113487931,
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gnomAD: rs113487931,
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ClinVar: RCV000007747, RCV000032580, RCV000229649, RCV000421480, RCV001699177, RCV002490336
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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>Vulliamy et al. (2002) found a c.58G-A transition in the TERC gene in a 22-year-old man with telomere-related bone marrow failure (PFBMFT2; 614743), short stature, and phimosis with negative family history; and in 2 unrelated patients, a 5-year-old boy and a 53-year-old woman with nonsevere aplastic anemia and no indications of constitutional involvement. </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>.0005 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TERC, 72C-G
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<br />
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SNP: rs199422265,
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gnomAD: rs199422265,
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ClinVar: RCV000007748, RCV000032581
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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>Vulliamy et al. (2002) found a c.72C-G transversion in the TERC gene in a 33-year-old man with telomere-related bone marrow failure (PFBMFT2; 614743) and severe osteoporosis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TERC, 4-BP DEL, 110GACT
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<br />
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|
|
|
SNP: rs199422270,
|
|
|
|
|
|
|
|
ClinVar: RCV000007749, RCV000032556, RCV001214506
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old man and his sister with telomere-related bone marrow failure (PFBMFT2; 614743), Vulliamy et al. (2002) found a 4-bp deletion (c.110-113GACT) in the TERC gene. </p>
|
|
</span>
|
|
</div>
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|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 116C-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422272,
|
|
|
|
|
|
|
|
ClinVar: RCV000007750, RCV000032559, RCV001818142, RCV002509148
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families in which an adult was initially diagnosed with acquired aplastic anemia, Fogarty et al. (2003) identified heterozygous point mutations in the TERC gene in affected members of both families: a c.116C-T transition in the pseudoknot domain (CR2/CR3) in 1 family, and a c.204C-G transversion (602322.0008) in the other. Affected members of both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin (PFBMFT2; 614743). Neither mutation was found in 194 phenotypically normal individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 204C-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422277,
|
|
|
|
|
|
|
|
ClinVar: RCV000007746, RCV000032564
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families in which an adult was initially diagnosed with acquired aplastic anemia, Fogarty et al. (2003) identified heterozygous point mutations in the TERC gene in affected members of both families: a c.116C-T transition (602322.0007) in the pseudoknot domain (CR2/CR3) in 1 family, and a c.204C-G transversion in the other. Affected members of both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin (PFBMFT2; 614743). Neither mutation was found in 194 phenotypically normal individuals. </p><p>Parry et al. (2011) identified a heterozygous c.204C-G transversion in the TERC gene in 3 members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure-2. The telomere length in mutation carriers was less than 1% of control, and the mutation was demonstrated to result in compromised telomerase activity. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PULMONARY FIBROSIS AND BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 98G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422268,
|
|
|
|
|
|
|
|
ClinVar: RCV000007751, RCV000032584
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female nonsmoker with telomere-related pulmonary fibrosis (PFBMFT2; 614743) who was diagnosed at 60 years of age and who died at age 66 years, Armanios et al. (2007) identified heterozygosity for a c.98G-A transition at a highly conserved site in the TERC gene, predicted to impair base pairing in a helix of the essential pseudoknot domain. Reconstitution of telomerase with the mutant 98A allele revealed severe impairment of activity. The mutation was not found in 194 healthy controls. Six family members had died of pulmonary fibrosis, including the proband's mother; 3 died from aplastic anemia, and 1 individual died from acute myeloid leukemia, probably in the setting of aplastic anemia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 325G-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1777959964,
|
|
|
|
|
|
|
|
ClinVar: RCV000007752
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with telomere-related pulmonary fibrosis (PFBMFT2; 614743), Alder et al. (2008) identified heterozygosity for a 325G-T transversion in the TERC gene, predicted to disrupt the conserved P5 helix. Younger asymptomatic sibs of the proband also carried the mutation, which was associated with short telomeres and led to a loss of activity as quantitated by the direct telomerase activity assay. The mutation was not found in 194 healthy controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 4-BP DEL, NT54
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422263,
|
|
|
|
|
|
|
|
ClinVar: RCV000023192, RCV003480035
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 7 members of a Dutch family with autosomal dominant dyskeratosis congenita (DKCA1; 127550), Jongmans et al. (2012) identified a heterozygous 4-bp deletion (c.54_57del) in the TERC gene. The proband was a 26-year-old man with multiple features of the disorder, including dystrophic nails, reticular pigmentation of the neck and chest, gray lock of hair, aplastic anemia, pulmonary fibrosis, liver disease, and avascular necrosis of the hip. The family history was positive for pulmonary fibrosis, cirrhosis, and aplastic anemia. Although the mutation segregated with the disease, the mutation load was decreased in blood of the proband's father and the father's brother, both of whom had disease limited to pulmonary fibrosis. The findings suggested somatic reversion of the mutated allele to a normal state. SNP analysis of the blood from the father and uncle showed that both had an acquired uniparental disomy of chromosome 3q, including the TERC gene. Detailed blood analysis of 1 of the brothers showed 2 different mosaic reversion patterns in B cells, granulocytes, and monocytes. T cells showed heterozygous levels of the mutant allele, consistent with the longer lifespan of these cells. Thus, mitotic recombination explained the reversion and phenotypic variability in the brothers. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 143G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422274,
|
|
|
|
|
|
|
|
ClinVar: RCV000032561, RCV001610304
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a family spanning 3 generations with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-2 (PFBMFT2; 614743), Parry et al. (2011) identified a heterozygous c.143G-A transition in the TERC gene. One patient had pulmonary fibrosis, 1 had pulmonary fibrosis and liver disease, and 1 had bone marrow failure. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TERC, 212C-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2108183105,
|
|
|
|
|
|
|
|
ClinVar: RCV000030634
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son with telomere-related bone marrow failure (PFBMFT2; 614743), Kirwan et al. (2009) identified a heterozygous c.212C-G transversion in the TERC gene. The son had severe aplastic anemia, whereas the father presented with myelodysplastic syndrome at age 45 years. In vitro studies showed less than 1% telomerase activity, and telomeres in the father were very short. The findings suggested that constitutional TERC mutations are associated with the development of myelodysplastic syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Agarwal, S., Loh, Y.-H., McLoughlin, E. M., Huang, J., Park, I-H., Miller, J. D., Huo, H., Okuka, M., dos Reis, R. M., Loewer, S., Hg, H.-H., Keefe, D. L., Goldman, F. D., Klingelhutz, A. J., Liu, L., Daley, G. Q.
|
|
<strong>Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.</strong>
|
|
Nature 464: 292-296, 2010.
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|
|
|
|
|
[PubMed: 20164838]
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|
|
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|
|
[Full Text: https://doi.org/10.1038/nature08792]
|
|
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|
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</p>
|
|
</li>
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|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Alder, J. K., Chen, J. J.-L., Lancaster, L., Danoff, S., Su, S., Cogan, J. D., Vulto, I., Xie, M., Qi, X., Tuder, R. M., Phillips, J. A., III, Lansdorp, P. M., Loyd, J. E., Armanios, M. Y.
|
|
<strong>Short telomeres are a risk factor for idiopathic pulmonary fibrosis.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 13051-13056, 2008.
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|
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|
[PubMed: 18753630]
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[Full Text: https://doi.org/10.1073/pnas.0804280105]
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|
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Armanios, M., Alder, J. K., Parry, E. M., Karim, B., Strong, M. A., Greider, C. W.
|
|
<strong>Short telomeres are sufficient to cause the degenerative defects associated with aging.</strong>
|
|
Am. J. Hum. Genet. 85: 823-832, 2009.
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|
|
[PubMed: 19944403]
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[Full Text: https://doi.org/10.1016/j.ajhg.2009.10.028]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Armanios, M. Y., Chen, J. J.-L., Cogan, J. D., Alder, J. K., Ingersoll, R. G., Markin, C., Lawson, W. E., Xie, M., Vulto, I., Phillips, J. A., III, Lansdorp, P. M., Greider, C. W., Loyd, J. E.
|
|
<strong>Telomerase mutations in families with idiopathic pulmonary fibrosis.</strong>
|
|
New Eng. J. Med. 356: 1317-1326, 2007.
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[PubMed: 17392301]
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[Full Text: https://doi.org/10.1056/NEJMoa066157]
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|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., DePinho, R. A.
|
|
<strong>Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.</strong>
|
|
Nature 406: 641-645, 2000.
|
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|
|
[PubMed: 10949306]
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|
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[Full Text: https://doi.org/10.1038/35020592]
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|
|
|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Baird, D. M., Rowson, J., Wynford-Thomas, D., Kipling, D.
|
|
<strong>Extensive allelic variation and ultrashort telomeres in senescent human cells.</strong>
|
|
Nature Genet. 33: 203-207, 2003.
|
|
|
|
|
|
[PubMed: 12539050]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1084]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ball, S. E., Gibson, F. M., Rizzo, S., Tooze, J. A., Marsh, J. C. W., Gordon-Smith, E. C.
|
|
<strong>Progressive telomere shortening in aplastic anemia.</strong>
|
|
Blood 91: 3582-3592, 1998.
|
|
|
|
|
|
[PubMed: 9572992]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Begus-Nahrmann, Y., Lechel, A., Obenauf, A. C., Nalapareddy, K., Peit, E., Hoffmann, E., Schlaudraff, F., Liss, B., Schirmacher, P., Kestler, H., Danenberg, E., Barker, N., Clevers, H., Speicher, M. R., Rudolph, K. L.
|
|
<strong>p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice.</strong>
|
|
Nature Genet. 41: 1138-1143, 2009.
|
|
|
|
|
|
[PubMed: 19718028]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.426]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., Greider, C. W.
|
|
<strong>Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.</strong>
|
|
Cell 91: 25-34, 1997.
|
|
|
|
|
|
[PubMed: 9335332]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(01)80006-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Box, J. A., Bunch, J. T., Tang, W., Baumann, P.
|
|
<strong>Spliceosomal cleavage generates the 3-prime end of telomerase RNA.</strong>
|
|
Nature 456: 910-914, 2008.
|
|
|
|
|
|
[PubMed: 19052544]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature07584]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cohen, S. B., Graham, M. E., Lovrecz, G. O., Bache, N., Robinson, P. J., Reddel, R. R.
|
|
<strong>Protein composition of catalytically active human telomerase from immortal cells.</strong>
|
|
Science 315: 1850-1853, 2007.
|
|
|
|
|
|
[PubMed: 17395830]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1138596]
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Comolli, L. R., Smirnov, I., Xu, L., Blackburn, E. H., James, T. L.
|
|
<strong>A molecular switch underlies a human telomerase disease.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 16998-17003, 2002.
|
|
|
|
|
|
[PubMed: 12482936]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.262663599]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cristofari, G., Adolf, E., Reichenbach, P., Sikora, K., Terns, R. M., Terns, M. P., Lingner, J.
|
|
<strong>Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation.</strong>
|
|
Molec. Cell 27: 882-889, 2007.
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Cassandra L. Kniffin - updated : 05/17/2023<br>Ada Hamosh - updated : 02/08/2016<br>Cassandra L. Kniffin - updated : 8/2/2012<br>Cassandra L. Kniffin - updated : 3/27/2012<br>Ada Hamosh - updated : 6/29/2011<br>Ada Hamosh - updated : 6/18/2010<br>Ada Hamosh - updated : 4/22/2010<br>Ada Hamosh - updated : 3/18/2010<br>Ada Hamosh - updated : 1/12/2010<br>Marla J. F. O'Neill - updated : 3/18/2009<br>Ada Hamosh - updated : 3/10/2009<br>Ada Hamosh - updated : 2/18/2009<br>Patricia A. Hartz - updated : 8/25/2008<br>Patricia A. Hartz - updated : 10/18/2007<br>Ada Hamosh - updated : 4/12/2007<br>Patricia A. Hartz - updated : 3/2/2007<br>Natalie E. Krasikov - updated : 8/10/2004<br>Victor A. McKusick - updated : 4/26/2004<br>Marla J. F. O'Neill - updated : 2/2/2004<br>Victor A. McKusick - updated : 2/20/2003<br>Victor A. McKusick - updated : 2/11/2003<br>Ada Hamosh - updated : 2/3/2003<br>Victor A. McKusick - updated : 2/3/2003<br>Stylianos E. Antonarakis - updated : 10/30/2001<br>Ada Hamosh - updated : 9/26/2001<br>Stylianos E. Antonarakis - updated : 9/8/2000<br>Victor A. McKusick - updated : 8/28/2000<br>Ada Hamosh - updated : 12/1/1999<br>Stylianos E. Antonarakis - updated : 8/31/1999<br>Stylianos E. Antonarakis - updated : 3/25/1999<br>Victor A. McKusick - updated : 5/27/1998<br>Victor A. McKusick - updated : 4/22/1998<br>Victor A. McKusick - updated : 4/7/1998
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Rebekah S. Rasooly : 2/9/1998
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alopez : 05/25/2023<br>ckniffin : 05/17/2023<br>alopez : 05/08/2023<br>alopez : 11/27/2019<br>ckniffin : 11/27/2019<br>carol : 03/20/2018<br>carol : 03/20/2018<br>carol : 08/23/2017<br>alopez : 02/08/2016<br>carol : 5/12/2015<br>carol : 8/6/2012<br>ckniffin : 8/2/2012<br>carol : 4/2/2012<br>ckniffin : 3/27/2012<br>alopez : 8/25/2011<br>alopez : 7/5/2011<br>alopez : 7/5/2011<br>terry : 6/29/2011<br>carol : 5/26/2011<br>ckniffin : 5/25/2011<br>alopez : 6/29/2010<br>terry : 6/18/2010<br>alopez : 4/26/2010<br>terry : 4/22/2010<br>alopez : 3/18/2010<br>wwang : 1/21/2010<br>wwang : 1/21/2010<br>alopez : 1/14/2010<br>terry : 1/12/2010<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>wwang : 3/23/2009<br>terry : 3/18/2009<br>alopez : 3/13/2009<br>terry : 3/10/2009<br>alopez : 2/20/2009<br>terry : 2/18/2009<br>terry : 9/10/2008<br>mgross : 8/26/2008<br>mgross : 8/26/2008<br>terry : 8/25/2008<br>mgross : 10/23/2007<br>terry : 10/18/2007<br>wwang : 7/9/2007<br>ckniffin : 6/12/2007<br>alopez : 4/13/2007<br>terry : 4/12/2007<br>mgross : 3/9/2007<br>terry : 3/2/2007<br>mgross : 11/17/2006<br>carol : 8/16/2005<br>carol : 1/5/2005<br>carol : 1/4/2005<br>carol : 8/10/2004<br>terry : 8/10/2004<br>terry : 6/18/2004<br>alopez : 5/3/2004<br>alopez : 4/27/2004<br>terry : 4/26/2004<br>joanna : 3/17/2004<br>carol : 2/2/2004<br>tkritzer : 5/7/2003<br>alopez : 2/28/2003<br>tkritzer : 2/20/2003<br>mgross : 2/14/2003<br>terry : 2/11/2003<br>alopez : 2/4/2003<br>alopez : 2/4/2003<br>terry : 2/3/2003<br>terry : 2/3/2003<br>carol : 2/6/2002<br>mgross : 10/30/2001<br>alopez : 9/26/2001<br>terry : 9/26/2001<br>mgross : 9/8/2000<br>alopez : 8/29/2000<br>terry : 8/28/2000<br>alopez : 12/1/1999<br>mgross : 8/31/1999<br>mgross : 3/31/1999<br>mgross : 3/26/1999<br>terry : 3/25/1999<br>alopez : 6/1/1998<br>terry : 5/27/1998<br>alopez : 4/22/1998<br>terry : 4/7/1998<br>alopez : 4/2/1998<br>alopez : 2/9/1998
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