Identification of multiple quantitative trait loci linked to prion disease incubation time.

Prion diseases are fatal neurodegenerative disorders which include sheep scrapie, bovine spongiform encephalopathy (BSE) and its human form, variant Creutzfeldt-Jakob disease (vCJD). Prion diseases have prolonged incubation times which are known to be affected by amino acid polymorphisms in the prion protein in humans, mice and sheep. In mice, Prnpa (Leu-108, Thr-189) and Prnpb (Phe-108, Val-189) are associated with short and long incubation times, respectively. However, studies with inbred lines of mice, all carrying Prnpa , show significant differences in incubation time suggesting that other genes contribute to this variation. To identify these loci we generated an F2 intercross between two Prnpa strains of mice with significantly different incubation times when inoculated intracerebrally with Chandler/RML scrapie prions. A whole genome screen was carried out in two stages using a total of 1009 F2 animals. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11 and 12 and composite interval mapping suggests that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7. We will also present data from another smaller F2 intercross using the same mouse strains but challenged with a different strain of prion: mouse adapted BSE