Positional Cloning of the Werner's Syndrome Gene

TLDR

Werner's syndrome is an inherited disorder characterized by premature aging symptoms and early susceptibility to major age‑related diseases. The WRN protein is a 1,432‑amino‑acid helicase‑like protein. Positional cloning identified the WRN gene, and four mutations—two splice‑junction, one homozygous frameshift truncation, and two nonsense—support a role for defective DNA metabolism in Werner's syndrome aging.

Abstract

Werner's syndrome (WS) is an inherited disease with clinical symptoms resembling premature aging. Early susceptibility to a number of major age-related diseases is a key feature of this disorder. The gene responsible for WS (known as WRN ) was identified by positional cloning. The predicted protein is 1432 amino acids in length and shows significant similarity to DNA helicases. Four mutations in WS patients were identified. Two of the mutations are splice-junction mutations, with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations, which results in a frameshift and a predicted truncated protein, was found in the homozygous state in 60 percent of Japanese WS patients examined. The other two mutations are nonsense mutations. The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.