Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.
Joseph M KelichTomas M AramburuJoanne J van der VisLouise ShoweAndrew V KossenkovJasper J van der SmagtMaarten MassinkAngela SchoemakerEric HennekamMarcel VeltkampColine H M van MoorselEmmanuel SkordalakesPublished in: The Journal of experimental medicine (2022)
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.
Keyphrases
- idiopathic pulmonary fibrosis
- dna damage
- gene therapy
- interstitial lung disease
- oxidative stress
- induced apoptosis
- diabetic rats
- dna repair
- case report
- high glucose
- early onset
- cell cycle arrest
- single cell
- big data
- gene expression
- endoplasmic reticulum stress
- genome wide
- dna methylation
- machine learning
- cell proliferation
- drug induced
- artificial intelligence
- dna binding
- data analysis