Werner syndrome is an autosomal recessive disease caused by inactivation of the gene encoding the DNA helicase WRN and is characterized by premature ageing, genomic instability and increased non-epithelial cancer incidence. It is thought that the erosion of telomeres — structures that cap chromosomes and are essential for chromosomal stability — has a role in the pathogenesis of this syndrome. Ron DePinho, Sandy Chang and colleagues have developed a mouse model that is null for both Wrn and the RNA component of telomerase ( Terc ) — an enzyme essential for telomere maintenance — that shows many of the classic features of Werner syndrome.

WRN is involved in DNA recombination, replication and repair, and hyper-recombination and numerous chromosomal aberrations have been observed in individuals with Werner syndrome. DePinho and Chang hypothesized that a combination of impaired DNA repair and telomere dysfunction might drive Werner syndrome pathogenesis.

The authors carried out successive intercrosses between Wrn−/− mice and Terc−/− mice to produce cohorts with progressively shorter telomeres and increasing telomere dysfunction. In first- and second-generation Terc−/− mice, Wrn status had no impact on clinical appearance, but the fourth- to sixth-generation Terc−/−Wrn−/− mice had lower body weights and shorter survival times than Terc−/−Wrn+/+ mice. Although healthy in early life, by 12–16 weeks of age many of the Terc−/−Wrn−/− mice had features of premature ageing, including Werner-syndrome-related diseases. Increased apoptosis in gastrointestinal crypt cells and increased numbers of fused chromosomes in bone-marrow cells were seen in successive generations of Terc−/−Wrn−/− mice. This reinforced a link between genomic instability due to WRN loss and telomere dysfunction.

So, how did these genotypes affect the cancer phenotype of these mice? The prematurely aged late-generation Terc−/−Wrn−/− mice were not particularly prone to cancer (presumably because they died before cancers developed), but the first- to third-generation Terc−/−Wrn−/− mice did have an increased incidence of osteosarcomas and soft-tissue sarcomas, usually developing at about 63 weeks. Terc−/−Wrn+/+ mice developed tumours later (around 85 weeks), and these were mainly lymphomas.

The study of this compound-mutant model of Werner syndrome supports the view that WRN is involved in telomere dynamics and that inactivation of this protein forms the basis of ageing phenotypes that target slowly proliferating mesenchymal tissues.