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Abstract

Abstract 

  1. Werner syndrome (WS) is a rare autosomal recessive disorder that is observed in many different ethnic groups. Prevalence estimates range from 1 in 22,000 to 1 in 1 million. All cases of WS are inherited and result from mutations in a single gene.

  2. WS is characterized clinically by the premature appearance of cataracts, scleroderma-like skin pathology, short stature, graying hair and hair loss, and a general appearance of premature aging. More variable features include adult-onset diabetes mellitus, hypogonadism, osteoporosis, osteosclerosis, soft tissue calcification, hyperkeratosis, ulcers on the feet and ankles, premature vascular disease, elevated rates of some neoplasms, a hoarse high-pitched voice, and flat feet. Subjects often appear 20 to 30 years older than their chronologic age, and WS may be a model disease for accelerated aging. The mean age at death is 47 years, with the leading cause being neoplasia, followed by myocardial infarcts and cerebral vascular incidents.

  3. WS subjects are at increased risk for a variety of neoplasms. This increased risk results primarily from an increase in non-epithelial-derived cancers and is not an across-the-board elevation in all common cancers. Soft tissue sarcomas, osteosarcomas, melanomas, and thyroid cancer are the predominant forms of cancer.

  4. The gene for WS (WRN), located on chromosome 8p12, has been cloned and encodes a 1432-amino acid protein (WRNp) that has homology to the super-family of DExH box DNA and RNA helicases; WRNp has the seven motifs found in this class of protein, including the ATP-binding and Mg2+-binding motifs. Outside the helicase domain, WRNp is homologous to an RNase D motif that may indicate a 3′→5′ proofreading exonuclease activity.

  5. Mutations have been identified in the WRN gene in all WS subjects studied. All the mutations result in a predicted truncated protein, the result of either a nonsense mutation or mutations leading to a frameshift. One splice-junction mutation is found in 50 to 60 percent of Japanese WS subjects. WS appears to be the result of loss of function of WRNp. No missense WS mutations have been found.

  6. In vitro, WRNp is a functional 3′→5′ DNA helicase. The in vivo function of WRNp is not known. WS is a genomic instability syndrome with elevated rates of chromosomal translocation and deletions and an elevated somatic cell mutation rate. This mutator phenotype, resulting from the loss of WRNp, could be a defect in an as yet unidentified DNA repair system, a defect in DNA replication initiation, or a defect in some other aspect of DNA metabolism that requires DNA unwinding.

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