Polymorphisms at codons 141 and 154 in the ovine prion protein gene are associated with scrapie Nor98 cases

Abstract

Until June 2004, thirty-eight scrapie cases with unusual features, designated Nor98, have been diagnosed in Norway. This study investigated the distribution of PrP genotypes among Nor98 cases, their flock-mates and a random sample of Norwegian slaughtered sheep. The PrP genotype distribution of Nor98 cases differed markedly from that of previous cases of classical scrapie. A leucine/phenylalanine polymorphism at codon 141 with hitherto unknown significance to scrapie was strongly associated with Nor98 cases. Twenty of 38 (52?6 %) cases were either homozygous or heterozygous for phenylalanine at codon 141. In contrast, this allele was present in only 10?5 % of the flock-mates and 4?5 % of the random sample of slaughtered sheep. Moreover, the H 154 allele was represented in 24 of 38 (63?2 %) of Nor98 cases, as opposed to 27?0 % of Nor98 flock-mates and 17?0 % of the slaughtered sheep.

Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology

“…Evidence so far indicates that atypical scrapie affects animals with PrP genotypes different from classical scrapie [2,3,9,26,27,29,30,33,36]. The appearance of atypical/Nor98 scrapie and classical scrapie in the same flock has not been reported as a common event, although there is no apparent genetic reason for this: indeed the separation of susceptible genotypes would perfectly permit infection with both diseases in an infected flock.…”

“…One of the first full descriptions of the PrP genetics for atypical/Nor98 scrapie was provided by Moum et al [30]. Performing fourcodon genotyping (codons 136, 141, 154, and 171) on 38 cases of Nor98 collected between 1998 and 2004, they came to three major conclusions.…”

“…We may then also be able to explain why the VRQ/AHQ genotype has a low risk for both types of scrapie, although it is composed of the two alleles with highest susceptibility risk for classical [3] and atypical/Nor98 [2,27,30,36] scrapie, respectively. The discovery of atypical/Nor98 scrapie has opened up a new phase in the exploration of the link between the PrP gene and disease, which in the end is likely to contribute fundamentally to the understanding of the underlying molecular mechanisms.…”

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

“…The AHQ, ARH, ARQ, and VRQ alleles are generally associated with susceptibility. The degree of, and the ranking for, susceptibility appears to be breed dependent, with the VRQ allele (when present within a breed) generally considered the most susceptible [7,8,31,44,61,64,77,79]. There is also evidence to suggest that polymorphisms at other codons within the PrP gene may modify the degree of resistance associated with the ARQ allele [82].…”

Cell models of prion infection

“…However, it is important to stress that PrP Cdependent susceptibility is not absolute and can vary depending on the strain of the agent. The newly described atypical sheep scrapie cases (Nor98, [10]) can infect sheep homozygous for ARR PrP C [18] and epidemiological data indicate that the more susceptible PrP C allele for atypical strains is not VRQ [123] but F141LARQ PrP C [93]. This emphasizes that PrP Cdependant genetic control of prion disease is a complex phenomenon that depends on both PrP C and the strain of the agent.…”