DIFFERENTIAL ALLELIC EXPRESSION OF PRP MESSENGER-RNA IN CARRIERS OF THE E200K MUTATION

Creutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the pr ion protein (PrP) gene presents with a wide range of age at disease on set. Since most patients are heterozygous for the mutation, we tested whether differential expression of mutant versus wild-type (wt) PrP ma y affect the age at disease onset in carriers of the mutation. We meas ured wt and mutant PrP protein and mRNA in Epstein-Barr virus (EBV)-tr ansformed B cells of either E200K CJD patients or healthy E200K carrie rs. Our results suggest that while in most healthy carriers the expres sion of wt PrP was higher than that of E200K PrP, most of the E200K CJ D patients express equal levels of both PrP proteins. Similar results were obtained for either PrP protein or PrP mRNA. These results sugges t that preferential expression of PrP from the wt allele may modulate the outbreak of the disease in carriers of prion mutations. This notio n is consistent with the results obtained in transgenic mice carrying a human PrP gene, which suggest that endogenous PrP protects mice from contracting scrapie after inoculation with human CJD brain. Similar m echanisms may prevail in other inherited diseases with variable phenot ypes.