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.(L2595). 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.

Automated summary

Exonic sequencing identified a previously unreported heterozygous mutation in POT1 p.(L2595) in a family with idiopathic pulmonary fibrosis (IPF). This mutation leads to telomere loss, DNA damage, and premature senescence in patient cells. The study reveals POT1(L259S) as a pathogenic driver of IPF and provides insights for potential gene therapy options.