Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that m ay be infectious, sporadic, or hereditary. The 200K point mutation in the P RNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutati on-associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide poly morphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD fami lies originating from 11 world populations. The results show that Libyan, T unisian, Italian, Chilean, and Spanish families share a major haplotype, su ggesting that the 200K mutation may have originated from a single mutationa l event, perhaps in Spain, and spread to all these populations with Sephard ic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Me diterranean or eastern European haplotypes. On the bais of this study, we c onclude that founder effect and independent mutational events are responsib le for the current geographic distribution of hereditary CJD associated wit h the 200K mutation.