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 a...

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Detalles Bibliográficos
Autores principales: Kelich, Joseph, Aramburu, Tomas, van der Vis, Joanne J., Showe, Louise, Kossenkov, Andrew, van der Smagt, Jasper, Massink, Maarten, Schoemaker, Angela, Hennekam, Eric, Veltkamp, Marcel, van Moorsel, Coline H.M., Skordalakes, Emmanuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014792/
https://www.ncbi.nlm.nih.gov/pubmed/35420632
http://dx.doi.org/10.1084/jem.20211681
Descripción
Sumario: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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