Molecular characterisation of instability in human telomere repeat arrays

Telomere instability was investigated at the proximal ends of human telomeres in normal and abnormal cells, with the aim to identify the frequency and types of mutations underlying telomere repeat turnover.;Analysis of the interspersion patterns of telomere and variant repeat types at the proximal ends of the 12q and Xp/Yp telomeres in human pedigrees gave a germline mutation frequency of 0.6% per telomere per gamete over the proximal 1kb of the telomere repeat array. No somatic telomere mutations were identified in normal fibroblast cells, but the upper limit for the mutation frequency was estimated as 7.468xlO-3 per cell. Each of 7 germline mutation events involved increases or decreases in small numbers of repeats. These events can be explained by intra-allelic mutational mechanisms, such as replication slippage and unequal sister-chromatid exchange. Localised telomere instability was associated with the CTAGGG variant repeat type in 6/7 germline mutations.;Approximately 15% of sporadic colon cancers and the majority of tumours from patients with hereditary non polyposis colon cancer (HNPCC) are caused by defects in genes involved in the mismatch repair pathway. Such defects result in an accummulation of mutations, particularly at microsatellite loci. A high mutation frequency was observed in the 12q and Xp/Yp telomere repeat arrays in colon cancers and was particularly associated with tumours showing microsatellite instability. The observed tumour mutations also involved increases or decreases in blocks of like-repeat types and can be explained by intra-allelic mutations. In one tumour, a complex telomere mutation was provisionally identified and may represent an inter-allelic mutation event.;No telomeric mutations were observed in the first kilobase of the 12q and Xp/Yp telomeres in cell-lines derived from patients suffering from the premature ageing disorder Werner syndrome. The lack of telomere mutations in Werner syndrome cells is discussed, with respect to overall telomere stability.