3079 lines
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Entry
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- *609377 - ACD SHELTERIN COMPLEX SUBUNIT AND TELOMERASE RECRUITMENT FACTOR; ACD
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- OMIM
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<p>
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<span class="h4">*609377</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</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/609377">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div 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 panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000102977;t=ENST00000620761" 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=65057" 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=609377" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000102977;t=ENST00000620761" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001082486,NM_001410884,NM_022914,XR_429728" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001082486" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=609377" 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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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=12417&isoform_id=12417_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/ACD" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/10435745,16877291,46102535,62422086,119603560,119603561,194375159,1407503537,1407503539,1746750943,2287478831" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q96AP0" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div 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=65057" 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=ENSG00000102977;t=ENST00000620761" 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=ACD" 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=ACD" 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+65057" 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/ACD" 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:65057" 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/65057" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000620761.6&hgg_start=67657512&hgg_end=67660260&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:25070" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:25070" 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=609377[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=609377[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000102977" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ACD" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ACD" 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=ACD" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ACD&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/PA134882431" 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:25070" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:87873" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ACD#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:87873" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/65057/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=65057" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-081022-45" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=ACD&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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609377
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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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ACD SHELTERIN COMPLEX SUBUNIT AND TELOMERASE RECRUITMENT FACTOR; ACD
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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">
|
|
ACD, MOUSE, HOMOLOG OF<br />
|
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POT1- AND TIN2-ORGANIZING PROTEIN; PTOP<br />
|
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POT1-INTERACTING PROTEIN 1; PIP1<br />
|
|
TIN2-INTERACTING PROTEIN 1; TINT1<br />
|
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TELOMERE PROTEIN TPP1
|
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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=ACD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ACD</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>
|
|
Cytogenetic location: <a href="/geneMap/16/554?start=-3&limit=10&highlight=554">16q22.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:67657512-67660260&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:67,657,512-67,660,260</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
|
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Phenotype
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</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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|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/16/554?start=-3&limit=10&highlight=554">
|
|
16q22.1
|
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</a>
|
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</span>
|
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</td>
|
|
|
|
|
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<td>
|
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<span class="mim-font">
|
|
?Dyskeratosis congenita, autosomal dominant 6
|
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|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616553"> 616553 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
?Dyskeratosis congenita, autosomal recessive 7
|
|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616553"> 616553 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
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</tbody>
|
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</table>
|
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/609377" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/609377" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
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</div>
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<p>The ACD gene encodes one of the core proteins in the telomeric shelterin complex; it is necessary for recruitment of telomerase (see TERT, <a href="/entry/187270">187270</a>) to telomeres (summary by <a href="#3" class="mim-tip-reference" title="Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. <strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong> Genes Dev. 28: 2090-2102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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.248567.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25233904">Kocak et al., 2014</a>, <a href="#1" class="mim-tip-reference" title="Guo, Y., Kartawinata, M., Li, J., Pickett, H. A., Teo, J., Kilo, T., Barbaro, P. M., Keating, B., Chen, Y., Tian, L., Al-Odaib, A., Reddel, R. R., Christodoulou, J., Xu, X., Hakonarson, H., Bryan, T. M. <strong>Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.</strong> Blood 124: 2767-2774, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25205116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25205116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25205116[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-2014-08-596445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25205116">Guo et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25233904+25205116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By database analysis and RT-PCR of HeLa cell mRNA, <a href="#4" class="mim-tip-reference" title="Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z. <strong>PTOP interacts with POT1 and regulates its localization to telomeres.</strong> Nature Cell Biol. 6: 673-680, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181449</a>] [<a href="https://doi.org/10.1038/ncb1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181449">Liu et al. (2004)</a> cloned PTOP. The deduced 544-amino acid protein contains a pro-trp-ile (PWI) motif, followed by a central POT1 (<a href="/entry/606478">606478</a>) recruitment domain and a serine-rich region. Compared with bovine, mouse, and pufferfish Ptop, human PTOP has an additional 86 N-terminal amino acids. By database analysis, <a href="#4" class="mim-tip-reference" title="Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z. <strong>PTOP interacts with POT1 and regulates its localization to telomeres.</strong> Nature Cell Biol. 6: 673-680, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181449</a>] [<a href="https://doi.org/10.1038/ncb1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181449">Liu et al. (2004)</a> identified 2 PTOP splice variants with in-frame deletions that encode proteins with deletions in the PWI domain or following the serine-rich region. PTOP was expressed in all human tissues examined. Immunofluorescence microscopy detected PTOP in a punctate pattern that colocalized with telomere proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The protein encoded by the ACD gene is sometimes referred to as TPP1. TPP1 is the HGNC approved gene symbol for tripeptidyl peptidase I (<a href="/entry/607998">607998</a>).</p>
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<p>By SDS-PAGE of fractionated HeLa cell nuclear extracts and immunoprecipitation analysis, <a href="#4" class="mim-tip-reference" title="Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z. <strong>PTOP interacts with POT1 and regulates its localization to telomeres.</strong> Nature Cell Biol. 6: 673-680, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181449</a>] [<a href="https://doi.org/10.1038/ncb1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181449">Liu et al. (2004)</a> found that PTOP was associated with endogenous TIN2 (TINF2; <a href="/entry/604319">604319</a>), POT1, and TRF2 (TERF2; <a href="/entry/602027">602027</a>) in a high-molecular-mass complex. Deletion analysis indicated that the C-terminal half of PTOP interacted with TIN2, whereas the central domain of PTOP interacted with the C-terminal half of POT1. PTOP was essential for targeting POT1 to telomeres, and expression of the POT1 recruitment domain of PTOP functioned in a dominant-negative manner, blocking the interaction of POT1 with telomeres and permitting telomere extension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ye, J. Z.-S., Hockemeyer, D., Krutchinsky, A. N., Loayza, D., Hooper, S. M., Chait, B. T., de Lange, T. <strong>POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex.</strong> Genes Dev. 18: 1649-1654, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15231715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15231715</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15231715[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.1215404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15231715">Ye et al. (2004)</a> found that PTOP, which they called PIP1, bound both POT1 and TIN2 and could tether POT1 to the TRF1 complex. Reduction of PTOP or POT1 levels with short hairpin RNAs led to telomere elongation, indicating that PTOP contributes to telomere length control through recruitment of POT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15231715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Through reconstitution and fractionation experiments, <a href="#7" class="mim-tip-reference" title="O'Connor, M. S., Safari, A., Xin, H., Liu, D., Songyang, Z. <strong>A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly.</strong> Proc. Nat. Acad. Sci. 103: 11874-11879, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880378[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.0605303103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880378">O'Connor et al. (2006)</a> found that TPP1 and TIN2 were essential mediators of telomeric complex formation and that TPP1-TIN2 interaction regulated bridging of TRF1 (TERF1; <a href="/entry/600951">600951</a>) and TRF2. Overexpression of TPP1 enhanced TIN2-TRF1 association, and conversely, knockdown of TPP1 reduced the ability of endogenous TRF1 to associate with the TRF2 complex. <a href="#7" class="mim-tip-reference" title="O'Connor, M. S., Safari, A., Xin, H., Liu, D., Songyang, Z. <strong>A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly.</strong> Proc. Nat. Acad. Sci. 103: 11874-11879, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880378[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.0605303103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880378">O'Connor et al. (2006)</a> concluded that coordinated interaction among TPP1, TIN2, TRF1, and TRF2 is required for assembly of the telomere complex and ultimately for telomere maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16880378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Xin, H., Liu, D., Wan, M., Safari, A., Kim, H., Sun, W., O'Connor, M. S., Songyang, Z. <strong>TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase.</strong> Nature 445: 559-562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237767</a>] [<a href="https://doi.org/10.1038/nature05469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237767">Xin et al. (2007)</a> demonstrated that TPP1 contains a predicted amino-terminal oligonucleotide/oligosaccharide-binding (OB) fold. TPP1-POT1 association enhanced POT1 affinity for telomeric single-stranded DNA. In addition, the TPP1 OB fold, as well as POT1-TPP1 binding, seemed critical for POT1-mediated telomere length control and telomere end protection in human cells. Disruption of POT1-TPP1 interaction by dominant-negative TPP1 expression or RNA interference resulted in telomere length alteration and DNA damage responses. Furthermore, <a href="#9" class="mim-tip-reference" title="Xin, H., Liu, D., Wan, M., Safari, A., Kim, H., Sun, W., O'Connor, M. S., Songyang, Z. <strong>TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase.</strong> Nature 445: 559-562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237767</a>] [<a href="https://doi.org/10.1038/nature05469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237767">Xin et al. (2007)</a> offered evidence that TPP1 associates with telomerase in a TPP1-OB-fold-dependent manner, providing a physical link between telomerase and the telosome/shelterin complex (a 6-protein complex thought to protect the telomeres of human chromosomes). <a href="#9" class="mim-tip-reference" title="Xin, H., Liu, D., Wan, M., Safari, A., Kim, H., Sun, W., O'Connor, M. S., Songyang, Z. <strong>TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase.</strong> Nature 445: 559-562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237767</a>] [<a href="https://doi.org/10.1038/nature05469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237767">Xin et al. (2007)</a> concluded that their findings highlighted the critical role of TPP1 in telomere maintenance, and supported a yin-yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Miyoshi, T., Kanoh, J., Saito, M., Ishikawa, F. <strong>Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length.</strong> Science 320: 1341-1344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18535244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18535244</a>] [<a href="https://doi.org/10.1126/science.1154819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18535244">Miyoshi et al. (2008)</a> reported that Tpz1, the TPP1 homolog in fission yeast, forms a complex with Pot1 (<a href="/entry/606478">606478</a>). Tpz1 binds to Ccq1 and Poz1 (Pot1-associated in Schizosaccharomyces pombe), which protect telomeres redundantly and regulate telomerase in positive and negative manners, respectively. Thus, <a href="#5" class="mim-tip-reference" title="Miyoshi, T., Kanoh, J., Saito, M., Ishikawa, F. <strong>Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length.</strong> Science 320: 1341-1344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18535244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18535244</a>] [<a href="https://doi.org/10.1126/science.1154819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18535244">Miyoshi et al. (2008)</a> concluded that the Pot1-Tpz1 complex accomplishes its functions by recruiting effector molecules Ccq1 and Poz1. Moreover, Poz1 bridges Pot1-Tpz1 and Taz1-Rap1, thereby connecting the single-stranded and double-stranded telomeric DNA regions. <a href="#5" class="mim-tip-reference" title="Miyoshi, T., Kanoh, J., Saito, M., Ishikawa, F. <strong>Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length.</strong> Science 320: 1341-1344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18535244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18535244</a>] [<a href="https://doi.org/10.1126/science.1154819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18535244">Miyoshi et al. (2008)</a> suggested that such molecular architectures are similar to those of mammalian shelterin, indicating that overall DNA-protein architecture is conserved across evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18535244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Nandakumar, J., Bell, C. F., Weidenfeld, I., Zaug, A. J., Leinwand, L. A., Cech, T. R. <strong>The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.</strong> Nature 492: 285-289, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23103865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23103865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23103865[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/nature11648" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23103865">Nandakumar et al. (2012)</a> identified separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The 7 separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these 2 activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a target for anticancer drug development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23103865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Wang, F., Podell, E. R., Zaug, A. J., Yang, Y., Baciu, P., Cech, T. R., Lei, M. <strong>The POT1-TPP1 telomere complex is a telomerase processivity factor.</strong> Nature 445: 506-510, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237768</a>] [<a href="https://doi.org/10.1038/nature05454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237768">Wang et al. (2007)</a> demonstrated the crystal structure of a domain of human TPP1 to reveal an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme telomerase. In contrast, <a href="#8" class="mim-tip-reference" title="Wang, F., Podell, E. R., Zaug, A. J., Yang, Y., Baciu, P., Cech, T. R., Lei, M. <strong>The POT1-TPP1 telomere complex is a telomerase processivity factor.</strong> Nature 445: 506-510, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237768</a>] [<a href="https://doi.org/10.1038/nature05454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237768">Wang et al. (2007)</a> found that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. <a href="#8" class="mim-tip-reference" title="Wang, F., Podell, E. R., Zaug, A. J., Yang, Y., Baciu, P., Cech, T. R., Lei, M. <strong>The POT1-TPP1 telomere complex is a telomerase processivity factor.</strong> Nature 445: 506-510, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237768</a>] [<a href="https://doi.org/10.1038/nature05454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237768">Wang et al. (2007)</a> proposed that POT1-TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z. <strong>PTOP interacts with POT1 and regulates its localization to telomeres.</strong> Nature Cell Biol. 6: 673-680, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181449</a>] [<a href="https://doi.org/10.1038/ncb1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181449">Liu et al. (2004)</a> stated that the ACD gene maps to chromosome 16q22.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Dyskeratosis Congenita 6, Autosomal Dominant</em></strong></p><p>
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In 3 female members in 3 subsequent generations of a family with autosomal dominant dyskeratosis congenita-6 (DKCA6; <a href="/entry/616533">616533</a>) manifest as progressive bone marrow failure, <a href="#1" class="mim-tip-reference" title="Guo, Y., Kartawinata, M., Li, J., Pickett, H. A., Teo, J., Kilo, T., Barbaro, P. M., Keating, B., Chen, Y., Tian, L., Al-Odaib, A., Reddel, R. R., Christodoulou, J., Xu, X., Hakonarson, H., Bryan, T. M. <strong>Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.</strong> Blood 124: 2767-2774, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25205116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25205116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25205116[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-2014-08-596445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25205116">Guo et al. (2014)</a> identified a heterozygous in-frame 3-bp deletion in the ACD gene (K140del; <a href="#0001">609377.0001</a>). Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres. The findings indicated that a defect in TPP1 renders telomerase unable to maintain telomeres during development and hematopoiesis, leading to short telomeres and progressive bone marrow failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25205116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Dyskeratosis Congenita 7, Autosomal Recessive</em></strong></p><p>
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In a boy with autosomal recessive dyskeratosis congenita-7 (DKCB7; see <a href="/entry/616553">616553</a>), <a href="#3" class="mim-tip-reference" title="Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. <strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong> Genes Dev. 28: 2090-2102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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.248567.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25233904">Kocak et al. (2014)</a> identified compound heterozygous mutations in the ACD gene: K170del and P491T (<a href="#0002">609377.0002</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father and sister, who had short telomeres, were heterozygous for the K170del mutation; the patient's mother, who was unaffected, was heterozygous for the missense mutation. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; <a href="/entry/602322">602322</a>) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (<a href="/entry/604319">604319</a>) association. <a href="#3" class="mim-tip-reference" title="Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. <strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong> Genes Dev. 28: 2090-2102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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.248567.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25233904">Kocak et al. (2014)</a> concluded that the detrimental effect of the P491T mutation was modest compared to the effect of the K170del mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25233904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the urogenital ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. <a href="#2" class="mim-tip-reference" title="Keegan, C. E., Hutz, J. E., Else, T., Adamska, M., Shah, S. P., Kent, A. E., Howes, J. M., Beamer, W. G., Hammer, G. D. <strong>Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator.</strong> Hum. Molec. Genet. 14: 113-123, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15537664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15537664</a>] [<a href="https://doi.org/10.1093/hmg/ddi011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15537664">Keegan et al. (2005)</a> identified a splice donor mutation in the Acd gene in acd mice. Expression of a wildtype Acd transgene in acd mutants rescued the observed phenotype. Most mutants died within 1 to 2 days of life on the original genetic background. Analysis of mutant embryos revealed variable defects in caudal specification, limb patterning, and axial skeleton formation. In the tail bud, reduced expression of Wnt3a (<a href="/entry/606359">606359</a>) and DLL1 (<a href="/entry/606582">606582</a>) correlated with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 (<a href="/entry/600483">600483</a>) was expanded in the dorsal-ventral axis of the apical ectodermal ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos showed abnormal vertebral fusions in cervical, lumbar, and caudal regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15537664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs797045144 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045144;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=rs797045144" 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=rs797045144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><strong><em>Dyskeratosis Congenita, Autosomal Dominant 6</em></strong></p><p>
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In 3 female members in 3 subsequent generations of a family with autosomal dominant dyskeratosis congenita-6 (DKCA6; <a href="/entry/616553">616553</a>) manifest as progressive bone marrow failure, <a href="#1" class="mim-tip-reference" title="Guo, Y., Kartawinata, M., Li, J., Pickett, H. A., Teo, J., Kilo, T., Barbaro, P. M., Keating, B., Chen, Y., Tian, L., Al-Odaib, A., Reddel, R. R., Christodoulou, J., Xu, X., Hakonarson, H., Bryan, T. M. <strong>Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.</strong> Blood 124: 2767-2774, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25205116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25205116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25205116[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-2014-08-596445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25205116">Guo et al. (2014)</a> identified a heterozygous in-frame 3-bp deletion (c.499_501del, NM_001082486.1) in the ACD gene, resulting in the deletion of conserved residue lys170 (K170del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in public databases. Lys170 localizes to the surface of the TPP1 protein known as the TEL patch, known to be vital for binding to telomerase. Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25205116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Dyskeratosis Congenita, Autosomal Recessive 7</em></strong></p><p>
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In a boy with autosomal recessive dyskeratosis congenita-7 (DKCB7; see <a href="/entry/616553">616553</a>) manifest as Hoyeraal-Hreidarsson syndrome, <a href="#3" class="mim-tip-reference" title="Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. <strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong> Genes Dev. 28: 2090-2102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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.248567.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25233904">Kocak et al. (2014)</a> identified compound heterozygous mutations in the ACD gene: a 3-bp deletion (c.508_510delAAG, NM_001082486.1), resulting in K170del, which was inherited from his father who had premature graying of the hair, short telomeres, and mild dental abnormalities, and a c.1471C-A transversion, resulting in a pro491-to-thr (P491T; <a href="#0002">609377.0002</a>) substitution at a conserved residue in the C-terminal TIN2-interacting domain, which was inherited from the unaffected mother. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The K170del mutation was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project (ESP) databases or in an in-house control database. The P401T variant was found in the dbSNP database and in the ESP database at a low frequency (0.0002), but was not present in the 1000 Genomes Project database or in the in-house control database. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; <a href="/entry/602322">602322</a>) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (<a href="/entry/604319">604319</a>) association. <a href="#3" class="mim-tip-reference" title="Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. <strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong> Genes Dev. 28: 2090-2102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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.248567.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25233904">Kocak et al. (2014)</a> concluded that the detrimental effect of the P491T mutation was modest compared to the effect of the K170del mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25233904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 7 (1 family)</strong>
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ACD, PRO491THR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201441120;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs201441120</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> rs201441120 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201441120;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/rs201441120?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=rs201441120" 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=rs201441120" 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=RCV000190905 OR RCV000225075 OR RCV002267926" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190905, RCV000225075, RCV002267926" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190905...</a>
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<p>For discussion of the c.1471C-A transversion in the ACD gene, resulting in a pro491-to-thr (P491T) substitution, that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-7 (DKCB7; <a href="/entry/616553">616553</a>) by <a href="#3" class="mim-tip-reference" title="Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. <strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong> Genes Dev. 28: 2090-2102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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.248567.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25233904">Kocak et al. (2014)</a>, see <a href="#0001">609377.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25233904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1182/blood-2014-08-596445" target="_blank">Full Text</a>]
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Keegan, C. E., Hutz, J. E., Else, T., Adamska, M., Shah, S. P., Kent, A. E., Howes, J. M., Beamer, W. G., Hammer, G. D.
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Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A.
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<strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong>
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Genes Dev. 28: 2090-2102, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25233904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25233904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25233904[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=25233904" 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/10.1101/gad.248567.114" target="_blank">Full Text</a>]
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Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181449</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181449" 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/ncb1142" target="_blank">Full Text</a>]
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Miyoshi, T., Kanoh, J., Saito, M., Ishikawa, F.
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[<a href="https://doi.org/10.1126/science.1154819" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature11648" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0605303103" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237768</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237768" 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/nature05454" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237767</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237767" 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/nature05469" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Ye2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ye, J. Z.-S., Hockemeyer, D., Krutchinsky, A. N., Loayza, D., Hooper, S. M., Chait, B. T., de Lange, T.
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<strong>POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex.</strong>
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Genes Dev. 18: 1649-1654, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15231715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15231715</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15231715[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=15231715" 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/10.1101/gad.1215404" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 9/17/2015
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 7/22/2013<br>Ada Hamosh - updated : 7/11/2008<br>Patricia A. Hartz - updated : 5/14/2008<br>George E. Tiller - updated : 10/31/2007<br>Ada Hamosh - updated : 4/25/2007<br>Patricia A. Hartz - updated : 9/15/2006
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 5/19/2005
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/10/2024
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<span class="mim-text-font">
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carol : 10/14/2021<br>carol : 10/13/2021<br>carol : 09/06/2019<br>joanna : 07/01/2016<br>carol : 6/24/2016<br>carol : 9/23/2015<br>alopez : 9/18/2015<br>alopez : 9/18/2015<br>ckniffin : 9/17/2015<br>ckniffin : 9/17/2015<br>alopez : 7/22/2013<br>alopez : 7/14/2008<br>terry : 7/11/2008<br>mgross : 5/14/2008<br>alopez : 11/6/2007<br>terry : 10/31/2007<br>alopez : 5/1/2007<br>terry : 4/25/2007<br>wwang : 9/19/2006<br>terry : 9/15/2006<br>mgross : 5/19/2005
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<h3>
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<span class="mim-font">
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<strong>*</strong> 609377
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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ACD SHELTERIN COMPLEX SUBUNIT AND TELOMERASE RECRUITMENT FACTOR; ACD
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</h3>
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ACD, MOUSE, HOMOLOG OF<br />
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POT1- AND TIN2-ORGANIZING PROTEIN; PTOP<br />
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POT1-INTERACTING PROTEIN 1; PIP1<br />
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TIN2-INTERACTING PROTEIN 1; TINT1<br />
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TELOMERE PROTEIN TPP1
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ACD</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 16q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:67,657,512-67,660,260 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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Phenotype
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Phenotype <br /> MIM number
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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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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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16q22.1
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<td>
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<span class="mim-font">
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?Dyskeratosis congenita, autosomal dominant 6
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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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616553
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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</tr>
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<td>
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<span class="mim-font">
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?Dyskeratosis congenita, autosomal recessive 7
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<span class="mim-font">
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616553
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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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>Description</strong>
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</h4>
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<span class="mim-text-font">
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<p>The ACD gene encodes one of the core proteins in the telomeric shelterin complex; it is necessary for recruitment of telomerase (see TERT, 187270) to telomeres (summary by Kocak et al., 2014, Guo et al., 2014). </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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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>By database analysis and RT-PCR of HeLa cell mRNA, Liu et al. (2004) cloned PTOP. The deduced 544-amino acid protein contains a pro-trp-ile (PWI) motif, followed by a central POT1 (606478) recruitment domain and a serine-rich region. Compared with bovine, mouse, and pufferfish Ptop, human PTOP has an additional 86 N-terminal amino acids. By database analysis, Liu et al. (2004) identified 2 PTOP splice variants with in-frame deletions that encode proteins with deletions in the PWI domain or following the serine-rich region. PTOP was expressed in all human tissues examined. Immunofluorescence microscopy detected PTOP in a punctate pattern that colocalized with telomere proteins. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The protein encoded by the ACD gene is sometimes referred to as TPP1. TPP1 is the HGNC approved gene symbol for tripeptidyl peptidase I (607998).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By SDS-PAGE of fractionated HeLa cell nuclear extracts and immunoprecipitation analysis, Liu et al. (2004) found that PTOP was associated with endogenous TIN2 (TINF2; 604319), POT1, and TRF2 (TERF2; 602027) in a high-molecular-mass complex. Deletion analysis indicated that the C-terminal half of PTOP interacted with TIN2, whereas the central domain of PTOP interacted with the C-terminal half of POT1. PTOP was essential for targeting POT1 to telomeres, and expression of the POT1 recruitment domain of PTOP functioned in a dominant-negative manner, blocking the interaction of POT1 with telomeres and permitting telomere extension. </p><p>Ye et al. (2004) found that PTOP, which they called PIP1, bound both POT1 and TIN2 and could tether POT1 to the TRF1 complex. Reduction of PTOP or POT1 levels with short hairpin RNAs led to telomere elongation, indicating that PTOP contributes to telomere length control through recruitment of POT1. </p><p>Through reconstitution and fractionation experiments, O'Connor et al. (2006) found that TPP1 and TIN2 were essential mediators of telomeric complex formation and that TPP1-TIN2 interaction regulated bridging of TRF1 (TERF1; 600951) and TRF2. Overexpression of TPP1 enhanced TIN2-TRF1 association, and conversely, knockdown of TPP1 reduced the ability of endogenous TRF1 to associate with the TRF2 complex. O'Connor et al. (2006) concluded that coordinated interaction among TPP1, TIN2, TRF1, and TRF2 is required for assembly of the telomere complex and ultimately for telomere maintenance. </p><p>Xin et al. (2007) demonstrated that TPP1 contains a predicted amino-terminal oligonucleotide/oligosaccharide-binding (OB) fold. TPP1-POT1 association enhanced POT1 affinity for telomeric single-stranded DNA. In addition, the TPP1 OB fold, as well as POT1-TPP1 binding, seemed critical for POT1-mediated telomere length control and telomere end protection in human cells. Disruption of POT1-TPP1 interaction by dominant-negative TPP1 expression or RNA interference resulted in telomere length alteration and DNA damage responses. Furthermore, Xin et al. (2007) offered evidence that TPP1 associates with telomerase in a TPP1-OB-fold-dependent manner, providing a physical link between telomerase and the telosome/shelterin complex (a 6-protein complex thought to protect the telomeres of human chromosomes). Xin et al. (2007) concluded that their findings highlighted the critical role of TPP1 in telomere maintenance, and supported a yin-yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA. </p><p>Miyoshi et al. (2008) reported that Tpz1, the TPP1 homolog in fission yeast, forms a complex with Pot1 (606478). Tpz1 binds to Ccq1 and Poz1 (Pot1-associated in Schizosaccharomyces pombe), which protect telomeres redundantly and regulate telomerase in positive and negative manners, respectively. Thus, Miyoshi et al. (2008) concluded that the Pot1-Tpz1 complex accomplishes its functions by recruiting effector molecules Ccq1 and Poz1. Moreover, Poz1 bridges Pot1-Tpz1 and Taz1-Rap1, thereby connecting the single-stranded and double-stranded telomeric DNA regions. Miyoshi et al. (2008) suggested that such molecular architectures are similar to those of mammalian shelterin, indicating that overall DNA-protein architecture is conserved across evolution. </p><p>Nandakumar et al. (2012) identified separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The 7 separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these 2 activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a target for anticancer drug development. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
|
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|
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<span class="mim-text-font">
|
|
<p>Wang et al. (2007) demonstrated the crystal structure of a domain of human TPP1 to reveal an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme telomerase. In contrast, Wang et al. (2007) found that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. Wang et al. (2007) proposed that POT1-TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Liu et al. (2004) stated that the ACD gene maps to chromosome 16q22.1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Dyskeratosis Congenita 6, Autosomal Dominant</em></strong></p><p>
|
|
In 3 female members in 3 subsequent generations of a family with autosomal dominant dyskeratosis congenita-6 (DKCA6; 616533) manifest as progressive bone marrow failure, Guo et al. (2014) identified a heterozygous in-frame 3-bp deletion in the ACD gene (K140del; 609377.0001). Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres. The findings indicated that a defect in TPP1 renders telomerase unable to maintain telomeres during development and hematopoiesis, leading to short telomeres and progressive bone marrow failure. </p><p><strong><em>Dyskeratosis Congenita 7, Autosomal Recessive</em></strong></p><p>
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In a boy with autosomal recessive dyskeratosis congenita-7 (DKCB7; see 616553), Kocak et al. (2014) identified compound heterozygous mutations in the ACD gene: K170del and P491T (609377.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father and sister, who had short telomeres, were heterozygous for the K170del mutation; the patient's mother, who was unaffected, was heterozygous for the missense mutation. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; 602322) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (604319) association. Kocak et al. (2014) concluded that the detrimental effect of the P491T mutation was modest compared to the effect of the K170del mutation. </p>
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<strong>Animal Model</strong>
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<p>Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the urogenital ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. Keegan et al. (2005) identified a splice donor mutation in the Acd gene in acd mice. Expression of a wildtype Acd transgene in acd mutants rescued the observed phenotype. Most mutants died within 1 to 2 days of life on the original genetic background. Analysis of mutant embryos revealed variable defects in caudal specification, limb patterning, and axial skeleton formation. In the tail bud, reduced expression of Wnt3a (606359) and DLL1 (606582) correlated with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 (600483) was expanded in the dorsal-ventral axis of the apical ectodermal ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos showed abnormal vertebral fusions in cervical, lumbar, and caudal regions. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>2 Selected Examples):</strong>
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<strong>.0001 DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 6 (1 family)</strong>
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DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 7, INCLUDED (1 family)
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ACD, 3-BP DEL, AAG
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SNP: rs797045144,
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ClinVar: RCV000190903, RCV000190904
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<p><strong><em>Dyskeratosis Congenita, Autosomal Dominant 6</em></strong></p><p>
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In 3 female members in 3 subsequent generations of a family with autosomal dominant dyskeratosis congenita-6 (DKCA6; 616553) manifest as progressive bone marrow failure, Guo et al. (2014) identified a heterozygous in-frame 3-bp deletion (c.499_501del, NM_001082486.1) in the ACD gene, resulting in the deletion of conserved residue lys170 (K170del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in public databases. Lys170 localizes to the surface of the TPP1 protein known as the TEL patch, known to be vital for binding to telomerase. Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres. </p><p><strong><em>Dyskeratosis Congenita, Autosomal Recessive 7</em></strong></p><p>
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In a boy with autosomal recessive dyskeratosis congenita-7 (DKCB7; see 616553) manifest as Hoyeraal-Hreidarsson syndrome, Kocak et al. (2014) identified compound heterozygous mutations in the ACD gene: a 3-bp deletion (c.508_510delAAG, NM_001082486.1), resulting in K170del, which was inherited from his father who had premature graying of the hair, short telomeres, and mild dental abnormalities, and a c.1471C-A transversion, resulting in a pro491-to-thr (P491T; 609377.0002) substitution at a conserved residue in the C-terminal TIN2-interacting domain, which was inherited from the unaffected mother. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The K170del mutation was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project (ESP) databases or in an in-house control database. The P401T variant was found in the dbSNP database and in the ESP database at a low frequency (0.0002), but was not present in the 1000 Genomes Project database or in the in-house control database. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; 602322) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (604319) association. Kocak et al. (2014) concluded that the detrimental effect of the P491T mutation was modest compared to the effect of the K170del mutation. </p>
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<span class="mim-font">
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<strong>.0002 DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 7 (1 family)</strong>
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<span class="mim-text-font">
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ACD, PRO491THR ({dbSNP rs201441120})
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SNP: rs201441120,
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gnomAD: rs201441120,
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ClinVar: RCV000190905, RCV000225075, RCV002267926
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<p>For discussion of the c.1471C-A transversion in the ACD gene, resulting in a pro491-to-thr (P491T) substitution, that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-7 (DKCB7; 616553) by Kocak et al. (2014), see 609377.0001. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Guo, Y., Kartawinata, M., Li, J., Pickett, H. A., Teo, J., Kilo, T., Barbaro, P. M., Keating, B., Chen, Y., Tian, L., Al-Odaib, A., Reddel, R. R., Christodoulou, J., Xu, X., Hakonarson, H., Bryan, T. M.
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<strong>Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.</strong>
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Blood 124: 2767-2774, 2014.
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[PubMed: 25205116]
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[Full Text: https://doi.org/10.1182/blood-2014-08-596445]
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Keegan, C. E., Hutz, J. E., Else, T., Adamska, M., Shah, S. P., Kent, A. E., Howes, J. M., Beamer, W. G., Hammer, G. D.
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<strong>Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator.</strong>
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Hum. Molec. Genet. 14: 113-123, 2005.
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[PubMed: 15537664]
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[Full Text: https://doi.org/10.1093/hmg/ddi011]
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Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A.
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<strong>Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.</strong>
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Genes Dev. 28: 2090-2102, 2014.
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[PubMed: 25233904]
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[Full Text: https://doi.org/10.1101/gad.248567.114]
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<li>
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<p class="mim-text-font">
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Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z.
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<strong>PTOP interacts with POT1 and regulates its localization to telomeres.</strong>
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Nature Cell Biol. 6: 673-680, 2004.
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[PubMed: 15181449]
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[Full Text: https://doi.org/10.1038/ncb1142]
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<p class="mim-text-font">
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Miyoshi, T., Kanoh, J., Saito, M., Ishikawa, F.
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<strong>Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length.</strong>
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Science 320: 1341-1344, 2008.
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[PubMed: 18535244]
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[Full Text: https://doi.org/10.1126/science.1154819]
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<p class="mim-text-font">
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Nandakumar, J., Bell, C. F., Weidenfeld, I., Zaug, A. J., Leinwand, L. A., Cech, T. R.
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<strong>The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.</strong>
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Nature 492: 285-289, 2012.
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[PubMed: 23103865]
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[Full Text: https://doi.org/10.1038/nature11648]
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<p class="mim-text-font">
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O'Connor, M. S., Safari, A., Xin, H., Liu, D., Songyang, Z.
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<strong>A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly.</strong>
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Proc. Nat. Acad. Sci. 103: 11874-11879, 2006.
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[PubMed: 16880378]
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[Full Text: https://doi.org/10.1073/pnas.0605303103]
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Wang, F., Podell, E. R., Zaug, A. J., Yang, Y., Baciu, P., Cech, T. R., Lei, M.
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<strong>The POT1-TPP1 telomere complex is a telomerase processivity factor.</strong>
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Nature 445: 506-510, 2007.
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[PubMed: 17237768]
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[Full Text: https://doi.org/10.1038/nature05454]
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<p class="mim-text-font">
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Xin, H., Liu, D., Wan, M., Safari, A., Kim, H., Sun, W., O'Connor, M. S., Songyang, Z.
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<strong>TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase.</strong>
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Nature 445: 559-562, 2007.
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[PubMed: 17237767]
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[Full Text: https://doi.org/10.1038/nature05469]
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Ye, J. Z.-S., Hockemeyer, D., Krutchinsky, A. N., Loayza, D., Hooper, S. M., Chait, B. T., de Lange, T.
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<strong>POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex.</strong>
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Genes Dev. 18: 1649-1654, 2004.
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[PubMed: 15231715]
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[Full Text: https://doi.org/10.1101/gad.1215404]
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Cassandra L. Kniffin - updated : 9/17/2015<br>Ada Hamosh - updated : 7/22/2013<br>Ada Hamosh - updated : 7/11/2008<br>Patricia A. Hartz - updated : 5/14/2008<br>George E. Tiller - updated : 10/31/2007<br>Ada Hamosh - updated : 4/25/2007<br>Patricia A. Hartz - updated : 9/15/2006
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Patricia A. Hartz : 5/19/2005
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carol : 09/10/2024<br>carol : 10/14/2021<br>carol : 10/13/2021<br>carol : 09/06/2019<br>joanna : 07/01/2016<br>carol : 6/24/2016<br>carol : 9/23/2015<br>alopez : 9/18/2015<br>alopez : 9/18/2015<br>ckniffin : 9/17/2015<br>ckniffin : 9/17/2015<br>alopez : 7/22/2013<br>alopez : 7/14/2008<br>terry : 7/11/2008<br>mgross : 5/14/2008<br>alopez : 11/6/2007<br>terry : 10/31/2007<br>alopez : 5/1/2007<br>terry : 4/25/2007<br>wwang : 9/19/2006<br>terry : 9/15/2006<br>mgross : 5/19/2005
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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