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Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk.

ABSTRACT: BACKGROUND: Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids including white-tailed (Odocoileus virginianus) and mule deer (Odocoileus hemionus), Rocky Mountain elk (Cervus elaphus nelsoni), and moose (Alces alces). A leucine variant at position 132 (132L) in prion protein of Rocky Mountain elk confers a long incubation time with CWD, but not complete resistance. However, variants in regulatory regions outside the open reading frame of PRNP have been associated with varying degrees of susceptibility to prion disease in other species, and some variants have been observed in similar regions of Rocky Mountain elk PRNP. Thus, additional genetic variants might provide increased protection, either alone or in combination with 132L. FINDINGS: This study provided genomic sequence of all exons for PRNP of Rocky Mountain elk. Many functional sites in and around the PRNP gene region were sequenced, and this report approximately doubled (to 75) the number of known variants in this region. A haplotype-tagging approach was used to reduce the number of genetic variants required to survey this variation in the PRNP gene region of 559 Rocky Mountain elk. Eight haplotypes were observed with frequencies over 1.0%, and one haplotype was present at 71.2% frequency, reflecting limited genetic diversity in the PRNP gene region. CONCLUSIONS: The presence of 132L cut odds of CWD by more than half (Odds Ratio = 0.43; P = 0.0031), which was similar to a previous report. However after accounting for 132L, no association with CWD was found for any additional variants in the PRNP region (P > 0.05).

SUBMITTER: White SN

PROVIDER: S-EPMC2994889 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk.

White Stephen N SN Spraker Terry R TR Reynolds James O JO O'Rourke Katherine I KI

BMC research notes 20101118

<h4>Background</h4>Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids including white-tailed (Odocoileus virginianus) and mule deer (Odocoileus hemionus), Rocky Mountain elk (Cervus elaphus nelsoni), and moose (Alces alces). A leucine variant at position 132 (132L) in prion protein of Rocky Mountain elk confers a long incubation time with CWD, but not complete resistance. However, variants in regulatory regions outside the open reading frame of PRNP have ...[more]

PMID: 21087518

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Project description:The Rocky Mountain elk (Cervus elaphus nelsoni) prion protein gene (PRNP) is polymorphic at codon 132, with leucine (L132) and methionine (M132) allelic variants present in the population. In elk experimentally inoculated with the chronic wasting disease (CWD) agent, different incubation periods are associated with PRNP genotype: LL132 elk survive the longest, LM132 elk are intermediate, and MM132 elk the shortest. The purpose of this study was to investigate potential mechanisms underlying variations in incubation period in elk of different prion protein genotypes. Elk calves of three PRNP genotypes (n =?2 MM132, n =?2 LM132, n =?4 LL132) were orally inoculated with brain homogenate from elk clinically affected with CWD.Elk with longer incubation periods accumulated relatively less PrPSc in the brain than elk with shorter incubation periods. PrPSc accumulation in LM132 and MM132 elk was primarily neuropil-associated while glial-associated immunoreactivity was prominent in LL132 elk. The fibril stability of PrPSc from MM132 and LM132 elk were similar to each other and less stable than that from LL132 elk. Real-time quaking induced conversion assays (RT-QuIC) revealed differences in the ability of PrPSc seed from elk of different genotypes to convert recombinant 132 M or 132 L substrate.This study provides further evidence of the importance of PRNP genotype in the pathogenesis of CWD of elk. The longer incubation periods observed in LL132 elk are associated with PrPSc that is more stable and relatively less abundant at the time of clinical disease. The biochemical properties of PrPSc from MM132 and LM132 elk are similar to each other and different to PrPSc from LL132 elk. The shorter incubation periods in MM132 compared to LM132 elk may be the result of genotype-dependent differences in the efficiency of propagation of PrPSc moieties present in the inoculum. A better understanding of the mechanisms by which the polymorphisms at codon 132 in elk PRNP influence disease pathogenesis will help to improve control of CWD in captive and free-ranging elk populations.

Project description:Chronic wasting disease (CWD) is a prion disease affecting cervids. Polymorphisms in the prion protein gene can result in extended survival of CWD-infected animals. However, the impact of polymorphisms on cellular prion protein (PrPC) and prion properties is less understood. Previously, we characterized the effects of a polymorphism at codon 116 (A>G) of the white-tailed deer (WTD) prion protein and determined that it destabilizes PrPC structure. Comparing CWD isolates from WTD expressing homozygous wild-type (116AA) or heterozygous (116AG) PrP, we found that 116AG-prions were conformationally less stable, more sensitive to proteases, with lower seeding activity in cell-free conversion and reduced infectivity. Here, we aimed to understand CWD strain emergence and adaptation. We show that the WTD-116AG isolate contains two different prion strains, distinguished by their host range, biochemical properties, and pathogenesis from WTD-116AA prions (Wisc-1). Serial passages of WTD-116AG prions in tg(CerPrP)1536+/+ mice overexpressing wild-type deer-PrPC revealed two populations of mice with short and long incubation periods, respectively, and remarkably prolonged clinical phase upon inoculation with WTD-116AG prions. Inoculation of serially diluted brain homogenates confirmed the presence of two strains in the 116AG isolate with distinct pathology in the brain. Interestingly, deglycosylation revealed proteinase K-resistant fragments with different electrophoretic mobility in both tg(CerPrP)1536+/+ mice and Syrian golden hamsters infected with WTD-116AG. Infection of tg60 mice expressing deer S96-PrP with 116AG, but not Wisc-1 prions induced clinical disease. On the contrary, bank voles resisted 116AG prions, but not Wisc-1 infection. Our data indicate that two strains co-existed in the WTD-116AG isolate, expanding the variety of CWD prion strains. We argue that the 116AG isolate does not contain Wisc-1 prions, indicating that the presence of 116G-PrPC diverted 116A-PrPC from adopting a Wisc-1 structure. This can have important implications for their possible distinct capacities to cross species barriers into both cervids and non-cervids.

Dataset Information

Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk.

Publications

Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk.

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