FATAL FAMILIAL INSOMNIA AND FAMILIAL CREUTZFELDT-JAKOB-DISEASE - DIFFERENT PRION PROTEINS DETERMINED BY A DNA POLYMORPHISM

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, tw o clinically and pathologically distinct diseases, are linked to the s ame mutation at codon 178 (Asp-178 --> Asn) but segregate with differe nt genotypes determined by this mutation and the methionine-valine pol ymorphism at codon 129 of the prion protein gene. The abnormal isoform s of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of th e protease-resistant fragments. The size difference was consistent wit h a different protease cleavage site, suggesting a different conformat ion of the protease-resistant prion protein present in the two disease s. These differences are likely to be responsible for the type and loc ation of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at c odon 129 determines the disease phenotype by producing two altered con formations of the prion protein.