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Scrapie is a prion disease in sheep that, similar to Kuru or variant Creutzfeldt-Jakob disease (vCJD), requires both prion exposure and a genetic susceptibility. Susceptibility is defined by amino acid polymorphisms in the single copy prion protein (PrP) gene, Prnp. Specifically, in sheep homozygous for A at position 136 and R at position 154, susceptibility is defined by R or Q at position 171. The genotype ARQ/ARQ confers susceptibility, whereas (apart from a few reported exceptions) genotypes ARR/ARQ and ARR/ARR confer resistance. Similarly, a M/V polymorphism at Prnp codon 129 determines susceptibility to vCJD and Kuru,4 with partial resistance conferred by the V allele. Assuming that overall PrP expression is not affected by genotype, two main alternatives for the resistance of heterozygous individuals exist: PrP ARR is preferentially expressed or PrP ARR interferes with the conversion of PrP ARQ to PrPsc. There is a precedence for both protein–protein interference and preferential allelic expression in genetic resistance to acquired and hereditary transmissible spongiform encephalopathies (TSEs), respectively. In the case of protein–protein interference, dominant negative inhibition can be defined as the ability of PrP expressed from a resistance associated allele to render conversion of PrP to PrPsc inefficient. It has been shown that C-terminal residues in PrP determine the ability of PrPc to convert to PrPsc on interaction with exogenous PrPsc,5 and it has been hypothesised that the affinity of PrPc to an endogenous cofactor (‘‘protein X’’) required for conversion accounts for this phenomenon. A putative binding region for protein X has been identified.