Joseph Kelich, Tomas Aramburu, Joanne J van der Vis, Louise Showe, Andrew Kossenkov, Jasper van der Smagt, Maarten Massink, Angela Schoemaker, Eric Hennekam, Marcel Veltkamp, Coline H M van Moorsel, Emmanuel Skordalakes
{"title":"Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.","authors":"Joseph Kelich, Tomas Aramburu, Joanne J van der Vis, Louise Showe, Andrew Kossenkov, Jasper van der Smagt, Maarten Massink, Angela Schoemaker, Eric Hennekam, Marcel Veltkamp, Coline H M van Moorsel, Emmanuel Skordalakes","doi":"10.1084/jem.20211681","DOIUrl":null,"url":null,"abstract":"<p><p>Exonic sequencing identified a family with idiopathic pulmonary fibrosis (IPF) containing a previously unreported heterozygous mutation in POT1 p.(L259S). The family displays short telomeres and genetic anticipation. We found that POT1(L259S) is defective in binding the telomeric overhang, nuclear accumulation, negative regulation of telomerase, and lagging strand maintenance. Patient cells containing the mutation display telomere loss, lagging strand defects, telomere-induced DNA damage, and premature senescence with G1 arrest. Our data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.</p>","PeriodicalId":20620,"journal":{"name":"Progress in Oceanography","volume":"21 1","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2022-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014792/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Progress in Oceanography","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1084/jem.20211681","RegionNum":3,"RegionCategory":"地球科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/4/14 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"OCEANOGRAPHY","Score":null,"Total":0}
引用次数: 0
Abstract
Exonic sequencing identified a family with idiopathic pulmonary fibrosis (IPF) containing a previously unreported heterozygous mutation in POT1 p.(L259S). The family displays short telomeres and genetic anticipation. We found that POT1(L259S) is defective in binding the telomeric overhang, nuclear accumulation, negative regulation of telomerase, and lagging strand maintenance. Patient cells containing the mutation display telomere loss, lagging strand defects, telomere-induced DNA damage, and premature senescence with G1 arrest. Our data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.
期刊介绍：
Progress in Oceanography publishes the longer, more comprehensive papers that most oceanographers feel are necessary, on occasion, to do justice to their work. Contributions are generally either a review of an aspect of oceanography or a treatise on an expanding oceanographic subject. The articles cover the entire spectrum of disciplines within the science of oceanography. Occasionally volumes are devoted to collections of papers and conference proceedings of exceptional interest. Essential reading for all oceanographers.
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