Transmission characteristics of heterozygous cases of Creutzfeldt-Jakob disease with variable abnormal prion protein allotypes

In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrP^C) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrP^Sc, by the pattern of PrP^Sc deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrP^Sc can have either a methionine (PrP^Sc-M129) or valine (PrP^Sc-V129) at residue 129. We have recently demonstrated that the relative amount of PrP^Sc-M129 versus PrP^Sc-V129, i.e. the PrP^Sc allotype ratio, varies between heterozygous CJD cases. In order to determine if differences in PrP^Sc allotype correlated with different disease phenotypes, we have inoculated 10 cases of heterozygous CJD (7 sporadic and 3 iatrogenic) into two transgenic mouse lines overexpressing PrP^C with a methionine at codon 129. In one case, brain-region specific differences in PrP^Sc allotype appeared to correlate with differences in prion disease transmission and phenotype. In the other 9 cases inoculated, the presence of PrP^Sc-V129 was associated with plaque formation but differences in PrP^Sc allotype did not consistently correlate with disease incubation time or neuropathology. Thus, while the PrP^Sc allotype ratio may contribute to diverse prion phenotypes within a single brain, it does not appear to be a primary determinative factor of disease phenotype.