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 was reported as approximately 54 years (Goto and colleagues' Japanese Werner registry analyses around 2000), and a 2022 retrospective study by Oshima and colleagues found mean age at death for patients dying between 2011 and 2020 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.