title: Is the prevalent human prion protein 129M/V   mutation a living fossil from a Paleolithic   panzootic superprion pandemic?
abstract: Prion diseases are consistently associated with prion protein (PrP(C)) misfolding rendering a cascade of auto-catalytic self-perpetuation of misfolded PrP in an afflicted individual. The molecular process is intriguingly similar to all known amyloid diseases both local and systemic. The prion disease is also infectious by the transfer of misfolded PrP from one individual to the next. Transmissibility is surprisingly efficient in prion diseases and given the rapid disease progression following initial symptoms the prionoses stand out from other amyloidoses, which all may be transmissible under certain circumstances. The nature of the infectious prion as well as the genotype of the host is important for transmissibility. For hitherto unexplained reasons the majority of Europeans carry a missense mutation on one or both alleles of the PrP gene (PRNP), and hence express a variant of PrP with a substitution for valine (V) instead of methionine (M) in position 129. In fact the 129M/V variant is very common in all populations except for the Japanese. Sporadic Creutzfeldt-Jakob disease is a disease rarely striking people below the age of 60, where homozygosity especially 129MM is a very strong risk factor. Paradoxically, the 129M/V polymorphism suggestive of heterozygote advantage is one of the most clear cut disease associated traits of the human population, yet prion disease is extraordinarily rare. The genetic basis for how this trait spread with such prevalence within human populations is still target to investigations and deserves attention. This short essay represents a somewhat provocative hypothetical notion of a possible ancient significance of this polymorphism.
authors.forename: Sofie
authors.initials: S
authors.lastname: Nyström
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
mesh_terms: D000686:Amyloidosis / Q000235:genetics; D005580:Fossils; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D017096:Prion Diseases / Q000453:epidemiology* / Q000235:genetics; D011328:Prions / Q000235:genetics*
chemical_list: D011328:Prions