Creutzfeldt~Jakob disease (CJD) is an inheritable and infectious disorder, and is prevalent in any population with a frequency of 1 per million; a portion of these cases are familial. We have studied 104 patients from 65 CJD~affected families. Two germ~line point mutations and an expanding 24~nucleotide repeat were identified in the PRNP gene on chromosome 20 in each of the familial CJD patients. Individuals carrying the mutated allele, but none of their siblings without a mutation, have eventually died of CJD. The Lod score for different mutations was 4.3 to 11 at a recombination fraction 0. CJD patients coming from high~incidence clusters of this disease in Czechoslovakia, Israel, and Chile all had a point mutation at codon 200 of the PRNP gene. In 10 studied cases of Gerstmann~Straussler~Sheinker syndrome (GSS), a point mutation in codon 102 of the PRNP gene was identified. Spongiform encephalopathy was transmitted to primates from 16 familial CJD patients with codon 200 mutation, 6 with codon 178 mutation, 3 with the expanding repeats, and 3 with GSS. Fatal familial insomnia (FFI) and familial CJD are distinct syndromes linked to the same 178 Asp substitution. Phenotypic expression is dependent on a """"""""neutral"""""""" polymorphism at codon 129: the 178 Asn+129 Met allele is responsible for FFI, whereas 178 Asn+129 Val have been found exclusively in the CJD variant. PrP protein is subject to a mutation~induced or spontaneous conformational change that makes it stable to protease degradation and capable of transforming virgin precursor molecules. These properties make PrP ~infectious~ and the disease transmissible. In our experiments, synthetic peptides homologous to several regions of the PrP sequence spontaneously formed amyloid fibrils with unique morphologic characteristics and polymerization tendencies. Peptides homologous to mutated regions of PrP exhibited enhanced fibrillogenic properties and, if mixed with the wild type peptide, produced even more abundant and larger fibrous aggregates which is viewed as the primary event leading to amyloid accumulation and disease.
