WERNER-SYNDROME - CHARACTERIZATION OF MUTATIONS IN THE WRN GENE IN ANAFFECTED FAMILY

Affected and unaffected members of a Caucasian family with Werner synd rome were analyzed for mutations in the recently described Werner synd rome (WRN) gene and for their relevance to phenotypic expression of ch romosomal instability and x-ray hypersensitivity. Two distinct molecul ar alterations were documented in the family, Analysis of the genomic DNA revealed a single-base exchange from A to T at an intron-exon boun dary in the otherwise strongly conserved 5' donor splice site. Consequ ently, exon 30 is spliced together with the intron, The ensuing struct ure could be confirmed by the presence and calculated size of the resu lting RNA fragments. The patients, all compound heterozygotes, had a l -bp deletion in the first third of the coding sequence in the other al lele. The genotypes of the family members for these mutations were det ermined and consequences for the cellular phenotype of the otherwise u naffected heterozygotes are documented.