A novel protective prion protein variant that colocalizes with kuru exposure.
BACKGROUND
Kuru is a devastating epidemic prion disease that affected a highly restricted geographic area of the Papua New Guinea highlands; at its peak, it predominantly affected adult women and children of both sexes. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism.


METHODS
We performed genetic and selected clinical and genealogic assessments of more than 3000 persons from Eastern Highland populations, including 709 who participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru.


RESULTS
Persons who were exposed to kuru and survived the epidemic in Papua New Guinea are predominantly heterozygotes at the known resistance factor at codon 129 of the prion protein gene (PRNP). We now report a novel PRNP variant--G127V--that was found exclusively in people who lived in the region in which kuru was prevalent and that was present in half of the otherwise susceptible women from the region of highest exposure who were homozygous for methionine at PRNP codon 129. Although this allele is common in the area with the highest incidence of kuru, it is not found in patients with kuru and in unexposed population groups worldwide. Genealogic analysis reveals a significantly lower incidence of kuru in pedigrees that harbor the protective allele than in geographically matched control families.


CONCLUSIONS
The 127V polymorphism is an acquired prion disease resistance factor selected during the kuru epidemic, rather than a pathogenic mutation that could have triggered the kuru epidemic. Variants at codons 127 and 129 of PRNP demonstrate the population genetic response to an epidemic of prion disease and represent a powerful episode of recent selection in humans.
Mead
Simon
S
Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, United Kingdom.
Whitfield
Jerome
J
Poulter
Mark
M
Shah
Paresh
P
Uphill
James
J
Campbell
Tracy
T
Al-Dujaily
Huda
H
Hummerich
Holger
H
Beck
Jon
J
Mein
Charles A
CA
Verzilli
Claudio
C
Whittaker
John
J
Alpers
Michael P
MP
Collinge
John
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D002190:Cannibalism; D004196:Disease Outbreaks; D005260:Female; D005787:Gene Frequency; D056084:Genetic Fitness; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007729:Kuru / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010219:Papua New Guinea / Q000453:epidemiology; D011110:Polymorphism, Genetic; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D055815:Young Adult
C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions