MUTATIONS IN THE CONSENSUS HELICASE DOMAINS OF THE WERNER SYNDROME GENE

Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mut ations in a gene, WRN, that encodes a predicted 1,432-amino-acid prote in with homology to DNA and RNA helicases. Previous work identified fo ur WS mutations in the 3' end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not dis rupt the helicase domain region (amino acids 569-859). Here, additiona l WS subjects were screened for mutations, and the intron-exon structu re of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutatio ns were identified: two nonsense mutations at codons 369 and 889; a mu tation at a splice-junction site, resulting in a predicted truncated p rotein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is > 15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially d isrupt the helicase domain region or result in predicted protein produ cts completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicas e domain does not influence the WS phenotype and suggests that WS is t he result of complete loss of function of the WRN gene product.