IDENTIFICATION OF THE WERNER'S SYNDROME GENE In the April 12, 96 issue of Science, Yu et al describe identification of the Werner’s syndrome gene. Werner’s syndrome (WS) is a rare disorder that leads to clinical manifestations that resemble premature aging in humans. This disease is inherited in an autosomal recessive fashion. Typically around the puberty, the affected individuals develop growth retardation. Among the other manifestations of this disease are premature graying of hair, loss of hair, atrophy of skin, several forms of arteriosclerosis, type II diabetes mellitus, osteoporosis, and cataracts. The lifespan of fibroblasts of WS patients is reduced and is comparable to those from aged individuals. The DNA metabolism seems to be defective in WS patients. Evidence for this aberrant DNA metabolism include, elevated rate of mutation of specific genes and nonhomologous recombination, chromosomal instability, decreased accuracy of ligation of disrupted plasmids and repair rate of telomeres, rapid decrease in telomere length, and possibly altered DNA replication. The cells of WS patients, however, do not show increased susceptibility to UV light or other DNA damaging insults, do not seem to be defective in nucleotide excision repair and do not exhibit an exchange rate of sister chromatid. In addition, the WS patients are not susceptible to Alzheimer’s diseases or hypertension that affect aged individuals. The WS gene called WRN codes for a 1432 amino acid protein that shows a significant homology to helicases. Four mutations are found in the WRN gene. Two of these mutations are splice-junction mutations which lead to the exclusion of the exons in the mature mRNA. One such mutation results in a frameshift and leads to formation of a truncated protein. Two other mutations are nonsense mutations. Helicases are involved in DNA replication, recombination, chromosome segregation, DNA repair, transcription or any function that requires unwinding of the DNA. In view of similarity to helicases, the WRN protein may exert similar functions in cells. Yu et al suggest that the consequence of the defect in WS patients may be the accumulation of DNA mutations that ultimately lead to the age-related manifestations of this disorder. Somatic mutations of oncogenes and tumor suppressor genes may be the underlying basis for the increased incidence of cancer seen in these patients. The DNA damage may also be responsible for premature replicative senescence and consequent pathologies. Whether the WRN gene is implicated in the normal aging process remains to be seen, however, the new discovery undoubtedly will shed light on the pathways that lead to the premature aging in patients with WS. REFERENCE: Chang-En Yu,Junko Oshima, Ying-Hui Fu, Ellen M. Wijsman, Fuki Hisama, Reid Alisch, Shellie Matthews, Jun Nakura, Tetsuro Miki: Positional Cloning of the Werner's Syndrome Gene. Science 272, 258-262, 1996