Variation in PrP prion gene sequence appears to modulate susceptibility to chronic wasting disease (CWD), a naturally occurring prion disease affecting four North American species of the family Cervidae. Wapiti (Cervus elaphus nelsoni ) PrP is polymorphic at codon 132 [methionine (M) or leucine (L)]. We genotyped 171 samples, collected between 2002 and 2005 from CWD-infected and uninfected wapiti from three free-ranging populations in Colorado, USA, to study influences of PrP polymorphisms on CWD susceptibility further. Overall genotype frequencies for 124 apparently uninfected animals were 65.3 % MM 132 , 32.3 % ML 132 and 2.4 % LL 132 ; for 47 CWD-infected animals, these frequencies were 70.2 % MM 132 , 27.7 % ML 132 and 2.1 % LL 132 . Surprisingly, our data revealed that, among recent (approx. 2002-2005) CWD cases detected in free-ranging Colorado wapiti, the three PrP codon 132 genotypes were represented in proportion to their abundance in sampled populations (P¢0.24) and all three genotypes showed equivalent susceptibility to infection.Chronic wasting disease (CWD) is a naturally occurring transmissible spongiform encephalopathy, or prion disease, that has been identified in four North American species of the family Cervidae: mule deer (Odocoileus hemionus) (Williams & Young, 1980), white-tailed deer (Odocoileus virginianus) (Spraker et al., 1997), wapiti (also called Rocky Mountain elk; Cervus elaphus nelsoni) (Williams & Young, 1982) and moose (Alces alces) (Baeten et al., 2007). The origin of CWD, its relationship to other prion diseases of mammalian species and factors influencing CWD epidemiology and susceptibility are not completely understood (Williams, 2005).In prion diseases of domestic ruminant hosts, PrP (prion protein) gene polymorphisms are associated with susceptibility and with the length of incubation periods (Baylis & Goldmann, 2004). A number of amino acid polymorphisms have been identified in the PrP gene from the four CWDaffected cervid species. Polymorphisms in the mule and white-tailed deer PrP gene have been found at codons 20, 65, 95, 96, 116, 225 and 226 (Heaton et al., 2003;Johnson et al., 2003;Jewell et al., 2005). Low levels of PrP variability have been identified in moose (at codon 209) (Huson & Happ, 2006) and wapiti (at codon 132) (O'Rourke et al., 1999).Wapiti PrP is polymorphic at codon 132, which corresponds to codon 129 in humans. The amino acid change in wapiti is from methionine (M) to leucine (L), whereas in humans it is to valine (V). The M129V polymorphism in the human PrP gene has been shown to have a major effect on susceptibility to, and phenotypic expression of, human prion diseases (Mead, 2006). Similarily, association with CWD susceptibility in free-ranging and farmed wapiti has been suggested, based on the findings that animals homozygous for methionine at codon 132 (MM 132 ) were over-represented in both free-ranging and farmed CWDaffected wapiti compared with healthy-control groups (O'Rourke et al., 1999;Spraker et al., 2004). We investigated genotype prof...

Susceptibility and incubation periods of transmissible spongiform encephalopathies, such as scrapie in sheep, are modulated by the PrP gene. The standard model of association between ovine PrP genetics and classical scrapie susceptibility is based on PrP genotypes with respect to codons 136, 154 and 171, e.g. alanine-arginine-glutamine (ARQ). It is demonstrated here that a proline to leucine substitution in codon 168 of the ovine PrP protein gene is associated with increased resistance to experimental bovine spongiform encephalopathy (BSE) inoculation. The ARL 168 Q PrP allele was found in heterozygous ARP 168 Q/ARL 168 Q sheep that have so far survived intravenous BSE challenge three times longer than BSE-challenged homozygous ARP 168 Q/ARP 168 Q sheep, which develop disease in around 700 days. In contrast, the L141F polymorphism does not appear to be associated with susceptibility to intravenous BSE challenge.Transmissible spongiform encephalopathies (TSEs) are fatal, neurodegenerative diseases occurring naturally in small ruminants as scrapie and in humans mainly as Creutzfeldt-Jakob disease. A main characteristic of these diseases is the conversion of the cellular PrP C (prion) protein to the abnormal, disease-associated isoform PrP Sc . Many mammals can be infected experimentally with TSEs and, in that way, it has been established that PrP protein variants modulate disease susceptibility and incubation periods (IPs) (reviewed by Bruce, 2003;.The ovine PrP coding region (comprising 256 codons) is highly polymorphic, with 27 polymorphic codons described to date. The current number of published haplotypes is 43. , 2006). It was found that the ARR allele is always associated with the longer IPs, whereas the VRQ, ARQ and AHQ alleles are associated with shorter IPs, but these differences depend on which TSE agent has been used (Goldmann et al., 1994). Susceptibility is also associated with these four PrP variants. Sheep that are highly susceptible to classical scrapie often carry the VRQ allele and resistant sheep have the ARR/ARR genotype. This resistance of ARR/ARR animals, however, can be overcome by intracerebral (i.c.) BSE challenge (Houston et al., 2003). The PrP gene association with TSEs established in experimental studies has been shown to be applicable to natural classical scrapie outbreaks in many breeds and is now part of UK and EUwide scrapie-eradication programmes (DEFRA, 2001).Recently, it was shown that reliance on only three PrP codon positions may not be sufficient to fully predict the susceptibility of sheep to TSE infection. Atypical scrapie has been described in several sheep flocks in several European countries. Most prominent are cases of Nor98 scrapie (Benestad et al., 2003), which were described to be associated with the L141F polymorphism (Moum et al., 2005). Even genotypes most resistant to classical scrapie, such as ARR/ARR, have been shown to contain deposits of abnormal PrP protein (Buschmann et al., 2004).Several new ovine PrP variants are discovered worldwide every year but, as...

The genetics of the prion protein gene (PRNP) play a crucial role in determining the relative susceptibility to transmissible spongiform encephalopathies (TSEs) in several mammalian species. To determine the PRNP gene variability in European red deer (Cervus elaphus), roe deer (Capreolus capreolus) and chamois (Rupicapra rupicapra), the PRNP open reading frame from 715 samples was analysed to reveal a total of ten single nucleotide polymorphisms (SNPs). In red deer, SNPs were found in codons 15, 21, 59, 78, 79, 98, 136, 168 and 226. These polymorphisms give rise to 12 haplotypes, and one of which is identical to the PRNP of American wapiti (Rocky Mountain elk, Cervus elaphus nelsoni). One silent mutation at codon 119 was detected in chamois and no SNPs were found in roe deer. This analysis confirmed that European wild ruminants have a PRNP genetic background that is compatible with TSE susceptibility, including chronic wasting disease.

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