The first report of a strong association between genetic polymorphisms of the prion protein gene (PRNP) and susceptibility to chronic wasting disease (CWD) in sika deer (Cervus nippon)
In-Soon Roh,Yong-Chan Kim,Sae-Young Won,Min-Ju Jeong,Kyung-Je Park,Hoo-Chang Park,Yu-Ran Lee,Hae-Eun Kang,Hyun-Joo Sohn,Byung-Hoon Jeong First published: 29 March 2022 https://doi.org/10.1111/tbed.14543
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as https://doi.org/10.1111/tbed.14543
Abstract Prion diseases are incurable neurodegenerative disorders caused by proteinase K-resistant prion protein (PrPSc) derived from normal prion protein (PrPC) encoded by the prion protein gene (PRNP). Although the cervid PRNP gene plays a pivotal role in the pathological mechanism of chronic wasting disease (CWD), there is no existing association analysis between susceptibility to CWD and genetic polymorphisms of the PRNP gene in sika deer. We investigated genetic polymorphisms of the PRNP gene using amplicon sequencing in sika deer. In addition, to identify a genetic susceptibility factor, we compared genotype, allele and haplotype frequencies of the PRNP gene between CWD-positive and CWD-negative sika deer. Furthermore, to assess the effect of the genetic polymorphisms on sika deer prion protein (PrP), we performed in silico analysis using PolyPhen-2, PROVEAN and AMYCO. Finally, we analyzed the tertiary structure and electrostatic potential of sika deer PrP based on single nucleotide polymorphisms (SNPs) using the SWISS-MODEL and Swiss-PdbViewer programs. We found a total of 24 SNPs of the PRNP gene including 22 novel SNPs (10 synonymous SNPs and 12 non-synonymous SNPs) in sika deer. Among the non-synonymous SNPs, we found a strong association of the susceptibility to CWD with c.56G>A (Ser19Asn). In addition, we found that c.56G>A (Ser19Asn), c.296A>T (His99Leu) and c.560T>A (Val187Asp) were predicted to have damaging effects on sika deer PrP. Furthermore, we observed significant alterations in the electrostatic potential of sika deer PrP by genetic polymorphisms of the 187Asp allele. To the best of our knowledge, this was the first association study between genetic polymorphisms of the PRNP gene and susceptibility to CWD in sika deer.
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Published: 07 October 2021
Review on PRNP genetics and susceptibility to chronic wasting disease of Cervidae
Katayoun Moazami-Goudarzi, Olivier Andréoletti, Jean-Luc Vilotte & Vincent Béringue
Veterinary Research volume 52, Article number: 128 (2021) Cite this article
Abstract
To date, chronic wasting disease (CWD) is the most infectious form of prion disease affecting several captive, free ranging and wild cervid species. Responsible for marked population declines in North America, its geographical spread is now becoming a major concern in Europe. Polymorphisms in the prion protein gene (PRNP) are an important factor influencing the susceptibility to prions and their rate of propagation. All reported cervid PRNP genotypes are affected by CWD. However, in each species, some polymorphisms are associated with lower attack rates and slower progression of the disease. This has potential consequences in terms of genetic selection, CWD diffusion and strain evolution. CWD also presents a zoonotic risk due to prions capacity to cross species barriers. This review summarizes our current understanding of CWD control, focusing on PRNP genetic, strain diversity and capacity to infect other animal species, including humans.
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CWD positive animals with extended time before they succumb to disease likely represent a source of chronic prion shedding within populations and may contribute to environmental contamination.
***> CWD positive animals with extended time before they succumb to disease likely represent a source of chronic prion shedding within populations and may contribute to environmental contamination. <***
Genes (Basel) . 2021 Sep 10;12(9):1396. doi: 10.3390/genes12091396.
Selective Breeding for Disease-Resistant PRNP Variants to Manage Chronic Wasting Disease in Farmed Whitetail Deer
Nicholas Haley 1, Rozalyn Donner 1, Kahla Merrett 1, Matthew Miller 1, Kristen Senior 1
Affiliations expand
PMID: 34573378 DOI: 10.3390/genes12091396
Abstract
Chronic wasting disease (CWD) is a fatal transmissible spongiform encephalopathy (TSE) of cervids caused by a misfolded variant of the normal cellular prion protein, and it is closely related to sheep scrapie. Variations in a host's prion gene, PRNP, and its primary protein structure dramatically affect susceptibility to specific prion disorders, and breeding for PRNP variants that prevent scrapie infection has led to steep declines in the disease in North American and European sheep. While resistant alleles have been identified in cervids, a PRNP variant that completely prevents CWD has not yet been identified. Thus, control of the disease in farmed herds traditionally relies on quarantine and depopulation. In CWD-endemic areas, depopulation of private herds becomes challenging to justify, leading to opportunities to manage the disease in situ. We developed a selective breeding program for farmed white-tailed deer in a high-prevalence CWD-endemic area which focused on reducing frequencies of highly susceptible PRNP variants and introducing animals with less susceptible variants. With the use of newly developed primers, we found that breeding followed predictable Mendelian inheritance, and early data support our project's utility in reducing CWD prevalence. This project represents a novel approach to CWD management, with future efforts building on these findings.
Keywords: CWD; PRNP; deer; prion; resistance; selective breeding; susceptibility.
***> While resistant alleles have been identified in cervids, a PRNP variant that completely prevents CWD has not yet been identified.
In Moore et al., reindeer carrying allele E had longer survival-times following intracranial exposure [24]. In the same experiment, a reindeer with a genotype carrier of E, found dead without showing clinical signs ~13 months post-intracranial inoculation, had no histopathological lesions or PrPSc deposition at post-mortem examination.
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Our data support the notion that PRNP genetic variation modulates CWD susceptibility rather than conferring complete resistance. This is in agreement with experimental observations of reindeer-developing CWD after intracranial inoculation regardless of PRNP genotype [24].
***> Our data support the notion that PRNP genetic variation modulates CWD susceptibility rather than conferring complete resistance.
Published: 27 May 2021
White-tailed deer S96 prion protein does not support stable in vitro propagation of most common CWD strains
Alicia Otero, Camilo Duque Velásquez, Judd Aiken & Debbie McKenzie
Scientific Reports volume 11, Article number: 11193 (2021) Cite this article
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Abstract
PrPC variation at residue 96 (G/S) plays an important role in the epidemiology of chronic wasting disease (CWD) in exposed white-tailed deer populations. In vivo studies have demonstrated the protective effect of serine at codon 96, which hinders the propagation of common CWD strains when expressed in homozygosis and increases the survival period of S96/wt heterozygous deer after challenge with CWD. Previous in vitro studies of the transmission barrier suggested that following a single amplification step, wt and S96 PrPC were equally susceptible to misfolding when seeded with various CWD prions. When we performed serial prion amplification in vitro using S96-PrPC, we observed a reduction in the efficiency of propagation with the Wisc-1 or CWD2 strains, suggesting these strains cannot stably template their conformations on this PrPC once the primary sequence has changed after the first round of replication. Our data shows the S96-PrPC polymorphism is detrimental to prion conversion of some CWD strains. These data suggests that deer homozygous for S96-PrPC may not sustain prion transmission as compared to a deer expressing G96-PrPC.
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The protective effect of S96 and H95 alleles was further demonstrated by experimental oral infection in white-tailed deer expressing these amino acid substitutions19. Among the alleles of the PRNP gene associated with a lower CWD incidence and extended preclinical phase, S96 has the highest allelic frequency (~ 25%) after the wt allele in several white-tailed deer populations from the United States and Canada26,27,31. Subsequent independent transmission and epidemiological studies have demonstrated that deer homozygous and heterozygous for S96-PrPC are, compared to wt/wt deer, less susceptible to CWD infection, present prolonged survival times, show delayed prion accumulation and are generally at a significantly earlier stage of disease when deer herds are depopulated23,31,32,33.
***> Subsequent independent transmission and epidemiological studies have demonstrated that deer homozygous and heterozygous for S96-PrPC are, compared to wt/wt deer, less susceptible to CWD infection, present prolonged survival times,
Prion protein polymorphisms associated with reduced CWD susceptibility limit peripheral PrPCWD deposition in orally infected white-tailed deer
Alicia Otero1 , Camilo Duque Velásquez4,5, Chad Johnson3 , Allen Herbst2,5, Rosa Bolea1 , Juan José Badiola1 , Judd Aiken2,5 and Debbie McKenzie4,5*
Abstract
Background: Chronic wasting disease (CWD) is a prion disease affecting members of the Cervidae family. PrPC primary structures play a key role in CWD susceptibility resulting in extended incubation periods and regulating the propagation of CWD strains. We analyzed the distribution of abnormal prion protein (PrPCWD) aggregates in brain and peripheral organs from orally inoculated white-tailed deer expressing four different PRNP genotypes: Q95G96/ Q95G96 (wt/wt), S96/wt, H95/wt and H95/S96 to determine if there are substantial differences in the deposition pattern of PrPCWD between different PRNP genotypes.
Results: Although we detected differences in certain brain areas, globally, the different genotypes showed similar PrPCWD deposition patterns in the brain. However, we found that clinically affected deer expressing H95 PrPC , despite having the longest survival periods, presented less PrPCWD immunoreactivity in particular peripheral organs. In addition, no PrPCWD was detected in skeletal muscle of any of the deer.
Conclusions: Our data suggest that expression of H95-PrPC limits peripheral accumulation of PrPCWD as detected by immunohistochemistry. Conversely, infected S96/wt and wt/wt deer presented with similar PrPCWD peripheral distribution at terminal stage of disease, suggesting that the S96-PrPC allele, although delaying CWD progression, does not completely limit the peripheral accumulation of the infectious agent.
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The significantly longer incubation periods observed in deer with H95-PRNP alleles may not impact secretion of CWD (i.e., less CWD secreted over longer time periods). The emergence of new CWD strains could implicate a zoonotic potential [20].
Keywords: Prions, Prion diseases, Chronic wasting disease, CWD, PrPCWD, Peripheral tissues, Polymorphisms, Deer
***> Selective Breeding
***> less susceptible to CWD infection, present prolonged survival times...
this is very disturbing. with all the hype about selective breeding with different alleles, and presenting longer survival times with cwd, this would only allow the spreading of the cwd tse prion to last longer in the given environment imo., and as such has been stated in scientific literature...terry
With cervids, however, resistance based on the PRNP allele alone is not absolute, and is better characterized as a delayed progression [18,25]
Volume 23, Number 9—September 2017 Research Letter
Chronic Wasting Disease Prion Strain Emergence and Host Range Expansion
Allen Herbst1, Camilo Duque Velásquez1, Elizabeth Triscott, Judd M. Aiken, and Debbie McKenzieComments to Author Author affiliations: University of Alberta, Edmonton, Alberta, Canada
Abstract
Human and mouse prion proteins share a structural motif that regulates resistance to common chronic wasting disease (CWD) prion strains. Successful transmission of an emergent strain of CWD prion, H95+, into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains.
P-145 Estimating chronic wasting disease resistance in cervids using real time quaking- induced conversion
Nicholas J Haley1, Rachel Rielinqer2, Kristen A Davenport3, W. David Walter4, Katherine I O'Rourke5, Gordon Mitchell6, Juergen A Richt2 1 Department of Microbiology and Immunology, Midwestern University, United States; 2Department of Diagnostic Medicine and Pathobiology, Kansas State University; 3Prion Research Center; Colorado State University; 4U.S. Geological Survey, Pennsylvania Cooperative Fish and Wildlife Research Unit; 5Agricultural Research Service, United States Department of Agriculture; 6Canadian Food Inspection Agency, National and OlE Reference Laboratory for Scrapie and CWD
In mammalian species, the susceptibility to prion diseases is affected, in part, by the sequence of the host's prion protein (PrP). In sheep, a gradation from scrapie susceptible to resistant has been established both in vivo and in vitro based on the amino acids present at PrP positions 136, 154, and 171, which has led to global breeding programs to reduce the prevalence of scrapie in domestic sheep. In cervids, resistance is commonly characterized as a delayed progression of chronic wasting disease (CWD); at present, no cervid PrP allele conferring absolute resistance to prion infection has been identified. To model the susceptibility of various naturally-occurring and hypothetical cervid PrP alleles in vitro, we compared the amplification rates and efficiency of various CWD isolates in recombinant PrPC using real time quaking-induced conversion. We hypothesized that amplification metrics of these isolates in cervid PrP substrates would correlate to in vivo susceptibility - allowing susceptibility prediction for alleles found at 10 frequency in nature, and that there would be an additive effect of multiple resistant codons in hypothetical alleles. Our studies demonstrate that in vitro amplification metrics predict in vivo susceptibility, and that alleles with multiple codons, each influencing resistance independently, do not necessarily contribute additively to resistance. Importantly, we found that the white-tailed deer 226K substrate exhibited the slowest amplification rate among those evaluated, suggesting that further investigation of this allele and its resistance in vivo are warranted to determine if absolute resistance to CWD is possible.
***at present, no cervid PrP allele conferring absolute resistance to prion infection has been identified.
PRION 2016 CONFERENCE TOKYO
''There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.'' c) The commonest form of CJD occurs as a sporadic disease, the cause of which is unknown, although genetic factors (particularly the codon 129 polymorphism in the prion protein gene (PRNP)) influence disease susceptibility. The familial forms of human TSEs (see Box 1) appear to have a solely genetic origin and are closely associated with mutations or insertions in the PRNP gene. Most, but not all, of the familial forms of human TSEs have been transmitted experimentally to animals. There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.
''There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.''
c) The commonest form of CJD occurs as a sporadic disease, the cause of which is unknown, although genetic factors (particularly the codon 129 polymorphism in the prion protein gene (PRNP)) influence disease susceptibility. The familial forms of human TSEs (see Box 1) appear to have a solely genetic origin and are closely associated with mutations or insertions in the PRNP gene. Most, but not all, of the familial forms of human TSEs have been transmitted experimentally to animals. There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.
Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: Complement component C1q and Prnp polymorphisms§
Julie A. Blanchong a, *, Dennis M. Heisey b , Kim T. Scribner c , Scot V. Libants d , Chad Johnson e , Judd M. Aiken e , Julia A. Langenberg f , Michael D. Samuel g
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Identifying the genetic basis for heterogeneity in disease susceptibility or progression can improve our understanding of individual variation in disease susceptibility in both free-ranging and captive populations. What this individual variation in disease susceptibility means for the trajectory of disease in a population, however, is not straightforward. For example, the greater, but not complete, resistance to CWD in deer with at least one Serine (S) at amino acid 96 of the Prnp gene appears to be associated with slower progression of disease (e.g., Johnson et al., 2006; Keane et al., 2008a). If slower disease progression results in longer-lived, infected deer with longer periods of infectiousness, resistance may lead to increased disease transmission rates, higher prion concentrations in the environment, and increased prevalence, as has been observed in some captive deer herds (Miller et al., 2006; Keane et al., 2008a). Alternatively, if the slower progression of disease in resistant deer is not associated with longer periods of infectiousness, but might instead indicate a higher dose of PrPCWD is required for infection, transmission rates in the population could decline especially if, as in Wisconsin, deer suffer high rates of mortality from other sources (e.g., hunting). Clearly, determining the relationship between genetic susceptibility to infection, dose requirements, disease progression, and the period of PrPCWD infectiousness are key components for understanding the consequences of CWD to free-ranging populations.
Terry S. Singeltary Sr.
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