MOLECULAR-GENETIC STUDIES OF CREUTZFELDT-JAKOB-DISEASE

Genetic study of over 200 cases of Creutzfeldt-Jakob disease (CJD), Ge rstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (F FI), and kuru have brought a reliable body of evidence that the famili al forms of CJD and all known cases of GSS and FFI are linked to germl ine mutations in the coding region of the PRNP gene on chromosome 20, either point substitutions or expansion of the number of repeat units. No pathogenic mutations have so far been found in sporadic or infecti ous forms of CJD, although there are features of genetic predispositio n in iatrogenic CJD and kuru. in FFI and familial CJD, clinically and pathologically distinct syndromes that are both linked to the 178(Asp- ->Asn) substitution, phenotypic expression is dependent on a polymorph ism at codon 129. Synthetic peptides homologous to several regions of PrP spontaneously form insoluble amyloid fibrils with unique morpholog ical characteristics and polymerization tendencies. Peptides homologou s to mutated regions of PrP exhibit enhanced fibrilogenic properties a nd, if mixed with the wild-type peptide, produce even more abundant an d larger fibrous aggregates. A similar process in vivo may lead to amy loid accumulation and disease, and transmission of ''baby fibrils'' ma y induce disease in other hosts.