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":"特发性肺纤维化患者的端粒功能障碍与 POT1 有关。","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":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"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":"{\"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\":23015,\"journal\":{\"name\":\"The Tokushima journal of experimental medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"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\":\"The Tokushima journal of experimental medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1084/jem.20211681\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/4/14 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Tokushima journal of experimental medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1084/jem.20211681","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/4/14 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.
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.
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