GENETIC-ANALYSIS OF CREUTZFELDT-JAKOB-DISEASE AND RELATED DISORDERS

Genetic studies of over 200 cases of Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru have brought a reliable body of evidence that the fami lial forms of CJD and all known cases of css and FFI are linked to ger mline mutations in the coding region of the PRNP gene on chromosome 20 , either point substitutions or expansion of the number of 24-nucleoti de repeat units. Phenotypic expression of FFI and familial CJD, clinic ally and pathologically distinct syndromes linked to the 178Asp-->Asn substitution, is dependent on a polymorphism at codon 129. Synthetic p eptides homologous to several regions of PrP spontaneously form insolu ble amyloid fibrils with unique morphological characteristics and poly merization tendencies. Peptides homologous to mutated regions of PrP e xhibit enhanced fibrillogenic properties and, if mixed with the wild-t ype peptide, produce even more abundant and larger fibrous aggregates. A similar process in vivo may be the primary event leading to amyloid accumulation and disease.