WRN (Werner syndrome gene)

WRN encodes a member of the RecQ DNA helicase family with both helicase and exonuclease activities, involved in multiple DNA repair pathways including base excision repair, non-homologous end joining, and replication fork restart at sites of stalled polymerases. Biallelic loss-of-function mutations cause Werner syndrome, a segmental progeroid syndrome in which features of aging — including cataracts, atherosclerosis, type 2 diabetes, osteoporosis, and malignancies — appear in the third and fourth decades; median survival historically has been approximately 46 years, though a 2022 retrospective study found mean age at death had risen to approximately 59 years, likely reflecting improved management of malignancy and vascular disease. At the cellular level, WRN-deficient cells accumulate replication stress, telomere dysfunction, and genomic instability disproportionately rapidly. Werner syndrome is extensively studied as a model of accelerated aging, particularly to distinguish aging-driver from aging-bystander mechanisms, though the segmental nature of the phenotype means it does not recapitulate normal aging comprehensively.