Preventive or promotive effects of PRNP polymorphic heterozygosity on the onset of prion disease

The polymorphic heterozygosity of PRNP at codon 129 or 219 prevents the onset of sporadic Creutzfeldt-Jakob disease (sCJD). We investigated the association between polymorphic genotypes at codon 129 or 219 and comprehensive prion disease onset using non-CJD as a reference. EK heterozygotes at codon 219, versus EE homozygotes, showed a preventive effect on the extensive prion diseases―sCJD, genetic CJD (gCJD) with V180I or M232R mutation, and Gerstmann-Straussler-Scheinker disease with P102L mutation. No preventive effect was observed for E200K-gCJD and dura-grafted CJD (dCJD) in 129 MV and 219 EK heterozygotes. It was suggested that unlike other prion diseases, E200K-gCJD may not benefit from the preventive effect of 219 EK heterozygosity because complementary electrostatic interactions between PrP molecules at K200 and E219 might make homodimer formation easier. Comparison of sCJD and dCJD indicates that 219 EK heterozygosity strongly inhibits de novo synthesis of PrP(Sc) (initial PrP(Sc) formation), but does not inhibit accelerated propagation of existing PrP(Sc).