The prion protein-encoding gene (prnp) strongly influences the susceptibility of small ruminants to transmissible spongiform encephalopathies (TSEs). Hence, selective breeding programs have been implemented to increase sheep resistance to scrapie. For goats, epidemiological and experimental studies have provided some association between certain polymorphisms of the cellular prion protein (PrP^C) and resistance to TSEs. Among them, the Q/K polymorphism at PrP^C codon 222 (Q/K₂₂₂) yielded the most promising results. In this work, we investigated the individual effects of the K₂₂₂-PrP^C variant on the resistance/susceptibility of goats to TSEs. For that purpose, we generated two transgenic mouse lines, expressing either the Q₂₂₂ (wild type) or K₂₂₂ variant of goat PrP^C. Both mouse lines were challenged intracerebrally with a panel of TSE isolates. Transgenic mice expressing the wild-type (Q₂₂₂) allele were fully susceptible to infection with all tested isolates, whereas transgenic mice expressing similar levels of the K₂₂₂ allele were resistant to all goat scrapie and cattle BSE isolates but not to goat BSE isolates. Finally, heterozygous K/Q₂₂₂ mice displayed a reduced susceptibility to the tested panel of scrapie isolates. These results demonstrate a highly protective effect of the K₂₂₂ variant against a broad panel of different prion isolates and further reinforce the argument supporting the use of this variant in breeding programs to control TSEs in goat herds.

IMPORTANCE The objective of this study was to determine the role of the K₂₂₂ variant of the prion protein (PrP) in the susceptibility/resistance of goats to transmissible spongiform encephalopathies (TSEs). Results showed that transgenic mice expressing the goat K₂₂₂-PrP polymorphic variant are resistant to scrapie and bovine spongiform encephalopathy (BSE) agents. This protective effect was also observed in heterozygous Q/K₂₂₂ animals. Therefore, the single amino acid exchange from Q to K at codon 222 of the cellular prion protein provides resistance against TSEs. All the results presented here support the view that the K₂₂₂ polymorphic variant is a good candidate for selective breeding programs to control and eradicate scrapie in goat herds.