NR AOOO
AU Attwood,T.K.
TI A new dimension to the vCJD epidemic
QU Trends in Biotechnology 2001 Aug; 19(8): 283
PT Editorial
VT
In 1996, fears emerged that the human prion disease variant Creutzfeldt-Jakob Disease (vCJD) might correspond to infection with the agent of bovine spongiform encephalopathy (BSE). Research has since confirmed that BSE is indeed likely to have caused vCJD through alimentary contamination. Approximately one million contaminated cattle are thought to have entered the human food chain and, consequently, a major future epidemic of vCJD is predicted.
In prion diseases, polymorphisms in the prion protein (PrP) are known to influence incubation times. One polymorphism occurs in the human PrP gene (PRNP) at codon 129, which encodes either methionine or valine. To date, all cases of vCJD observed have arisen in methionine homozygous individuals. In mice, two PrP polymorphisms have been observed that are associated with short and long incubation times. However, although the role of such polymorphisms in incubation time is well known, there is evidence that PrP amino acid differences are not the only influence.
Prion incubation times in mice can be treated as a quantitative trait, the range of which depends on factors such as the route of infection, dose, prion strain, level of PrP expression and genetic susceptibility. To identify quantitative trait loci (QTL) for prion incubation times, Lloyd et al. [1] crossed two mouse strains that had identical PrP genotypes but significantly different incubation times. The progeny showed a range of incubation times, the upper limit of which was substantially greater than the parental maximum, suggesting a greater number of 'long' incubation time QTL in the offspring as a result of independent assortment of 'long' and 'short' alleles from both parents. Subsequent linkage analysis revealed chromosomes 2, 11 and 12 to have highly significant linkage, and multiple linked QTL were identified on all three chromosomes, which jointly explained 82% of the total variance of incubation times.
These results place doubt on the validity of genetic models used in epidemiological studies, which might underestimate the size of the vCJD epidemic by assuming that only methionine homozygotes are susceptible. This is unlikely because other human prion diseases, iatrogenic CJD and kuru, occur in all codon 129 genotypes, codon 129 heterozygotes having the longest incubation periods. Current vCJD patients must be those with the shortest BSE incubation times and are probably predominantly those with short incubation time alleles at multiple genetic loci in addition to having the codon 129 methionine-homozygous PRNP genotype; thus, they might represent a genetic subpopulation with atypically short prion incubation periods. Hence, the effect on susceptibility and incubation time of the mapped loci could be more significant than that exhibited by the PRNP locus itself. Further, because variation of prion incubation periods between mice increases when considering inter-species transmission, genes involved in the species barrier might also be relevant.
This study therefore challenges the use of current epidemiological predictions based only on early vCJD patients, demonstrating unequivocally that genetic loci other than the open reading frame of PRNP can dramatically influence murine prion disease incubation time. Identification of these loci in humans will hopefully allow more-robust predictions of epidemic parameters and contribute to a better understanding of prion pathogenesis.
1 Lloyd,S.E. (2001) Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc. Natl. Acad. Sci. U.S.A. 98, 6279-283
AD Teresa K. Attwood, attwood@bioinf.man.ac.uk
SP englisch
PO England