GENETIC-BASIS OF CREUTZFELDT-JAKOB-DISEASE IN THE UNITED-KINGDOM - A SYSTEMATIC ANALYSIS OF PREDISPOSING MUTATIONS AND ALLELIC VARIATION INTHE PRNP GENE

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative d isorder characterized by the accumulation of aggregates of a cellular protein, PrP, in the brain. In both human and animals, genetic alterat ions to the gene encoding PrP (PRNP in human) modulate susceptiblity t o CJD, The recent epidemic of bovine spongiform encephalopathy in the UK has raised the possibility of transmission from animal produce to h umans. To provide a baseline against which to assess possible risk fac tors, we have determined the frequencies of predisposing mutations and allelic variants in PRNP and their relative contributions to disease. Systematic PRNP genotype analysis was performed on suspected CJD case s referred to the National Surveillance Unit in the UK over the period 1990-1993. Inspection of 120 candidate cases revealed 67 patients wit h definite and probable CJD, based on clinical and neuropathological c riteria. No PRNP mutations were detected in any of the remaining 53 pa tients assessed as ''non-CJD''. A disease-associated mutation in the P RNP gene was identified in nine (13.4%) definite and probable cases of CJD, a reliable estimate of the incidence of PRNP-related inherited C JD based on a prospective epidemiological series. Within the group of sporadic CJD patients (lacking PRNP mutations), we confirmed that the genotype distribution with respect to the common methionine/valine (Me t/Val) polymorphism at codon 129 within PRNP was significantly differe nt from the normal Caucasian population, The incidence of Met homozygo sity at this site was more than doubled and correlated with increased susceptibility to the development of sporadic CJD. Unlike other recent studies, Val homozygosity was also confirmed to be a significant risk factor in sporadic CJD, with the relative risks for the three genotyp es Met/Met:Val/Val:Met/Val being 11:4:1.