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Stephen N. White - One of the best experts on this subject based on the ideXlab platform.
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Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk
BMC Research Notes, 2010Co-Authors: Stephen N. White, Terry R Spraker, James O Reynolds, Katherine I O'rourkeAbstract: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).
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prion gene PRNP haplotype variation in united states goat breeds open access publication
Genetics Selection Evolution, 2008Co-Authors: Katherine I Orourke, Janet Alverson, D. F. Waldron, Joan D Rowe, Stephen N. White, Lynn M HerrmannhoesingAbstract:Scrapie eradication efforts cost 18 million dollars annually in the United States and rely heavily upon PRNP genotyping of sheep. Genetic resistance might reduce goat scrapie and limit the risk of goats serving as a scrapie reservoir, so PRNP coding sequences were examined from 446 goats of 10 breeds, 8 of which had not been previously examined at PRNP. The 10 observed alleles were all related to one of two central haplotypes by a single amino acid substitution. At least five of these alleles (M142, R143, S146, H154, and K222) have been associated with increased incubation time or decreased odds of scrapie. To the best of our knowledge, neither S146 nor K222 has been found in any goats with scrapie, though further evaluation will be required to demonstrate true resistance. S146 was more common, present in several breeds at widely varying frequencies, while K222 was observed only in two dairy breeds at low frequency. Overall, this study provides frequency data on PRNP alleles in US goats, shows the pattern of relationships between haplotypes, and demonstrates segregation of multiple scrapieassociated alleles in several breeds not examined before at PRNP.
Katherine I O'rourke - One of the best experts on this subject based on the ideXlab platform.
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Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk
BMC Research Notes, 2010Co-Authors: Stephen N. White, Terry R Spraker, James O Reynolds, Katherine I O'rourkeAbstract: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).
Wilfred Goldmann - One of the best experts on this subject based on the ideXlab platform.
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Variation in the prion protein gene (PRNP) sequence of wild deer in Great Britain and mainland Europe
Veterinary Research, 2019Co-Authors: Amy L. Robinson, Helen Williamson, Mariella E. Güere, Helene Tharaldsen, Karis Baker, Stephanie L. Smith, Sílvia Pérez-espona, Jarmila Krojerová-prokešová, Josephine M. Pemberton, Wilfred GoldmannAbstract:AbstractSusceptibility to prion diseases is largely determined by the sequence of the prion protein gene (PRNP), which encodes the prion protein (PrP). The recent emergence of chronic wasting disease (CWD) in Europe has highlighted the need to investigate PRNP gene diversity in European deer species, to better predict their susceptibility to CWD. Here we report a large genetic survey of six British deer species, including red (Cervus elaphus), sika (Cervus nippon), roe (Capreolus capreolus), fallow (Dama dama), muntjac (Muntiacus reevesii), and Chinese water deer (Hydropotes inermis), which establishes PRNP haplotype and genotype frequencies. Two smaller data sets from red deer in Norway and the Czech Republic are also included for comparison. Overall red deer show the most PRNP variation, with non-synonymous/coding polymorphisms at codons 98, 168, 226 and 247, which vary markedly in frequency between different regions. Polymorphisms P168S and I247L were only found in Scottish and Czech populations, respectively. T98A was found in all populations except Norway and the south of England. Significant regional differences in genotype frequencies were observed within both British and European red deer populations. Other deer species showed less variation, particularly roe and fallow deer, in which identical PRNP gene sequences were found in all individuals analysed. Based on comparison with PRNP sequences of North American cervids affected by CWD and limited experimental challenge data, these results suggest that a high proportion of wild deer in Great Britain may be susceptible to CWD.
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prion protein gene polymorphisms in turkish native goat breeds
Journal of Genetics, 2017Co-Authors: Hasan Meydan, Mustafa Muhip Ozkan, Erkan Pehlivan, Mehmet Ali Yildiz, Wilfred GoldmannAbstract:Susceptibility to ‘scrapie’ disease in goats is influenced by polymorphisms of the prion protein (PRNP) gene. The aim of this study was to identify PRNP gene polymorphisms in a total of 356 scrapie disease-free goats from 10 Turkish native breeds. Eighteen single-nucleotide polymorphisms were detected in the caprine PRNP open-reading frame. Ten previously described amino acid substitutions (I142M, H143R, N146S, N146D, R151H, R154H, P168Q, R211Q, Q222K and P240S) and two novel dimorphisms (G134E and Q163P) were identified. The strongest association between caprine PRNP and relative resistance to scrapie disease has been reported previously for polymorphisms at codons 146 (S /D) and 222 (K). In the present study, these three PrP variants were relatively rare with 6.3%. This is the first report on PRNP gene variation in Turkish native goat breeds and our knowledge of these polymorphisms will assist goat breeding programmes to reduce the risk of scrapie.
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Caprine prion gene polymorphisms are associated with decreased incidence of classical scrapie in goat herds in the United Kingdom
Veterinary Research, 2011Co-Authors: Wilfred Goldmann, Otto Windl, Paula Stewart, Kelly Ryan, David Parnham, Rosa Xicohtencatl, Nora Fernandez, Ginny Saunders, Lorenzo González, Alex BossersAbstract:The application of genetic breeding programmes to eradicate transmissible spongiform encephalopathies in goats is an important aim for reasons of animal welfare as well as human food safety and food security. Based on the positive impact of PRNP genetics on sheep scrapie in Europe in the past decade, we have established caprine PRNP gene variation in more than 1100 goats from the United Kingdom and studied the association of PRNP alleles with disease phenotypes in 150 scrapie-positive goats. This investigation confirms the association of the Met142 encoding PRNP allele with increased resistance to preclinical and clinical scrapie. It reveals a novel association of the Ser127 encoding allele with a reduced probability to develop clinical signs of scrapie in goats that are already positive for the accumulation of disease-specific prion protein in brain or periphery. A United Kingdom survey of PRNP genotypes in eight common breeds revealed eleven alleles in over thirty genotypes. The Met142 encoding allele had a high overall mean allele frequency of 22.6%, whereas the Ser127 encoding allele frequency was considerably lower with 6.4%. In contrast, a well known resistance associated allele encoding Lys222 was found to be rare (0.9%) in this survey. The analysis of PRNP genotypes in Mexican Criollas goats revealed nine alleles, including a novel Phe to Leu substitution in codon 201, confirming that high genetic variability of PRNP can be found in scrapie-free populations. Our study implies that it should be feasible to lower scrapie prevalence in goat herds in the United Kingdom by genetic selection.
Christopher M Seabury - One of the best experts on this subject based on the ideXlab platform.
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disparate modes of evolution shaped modern prion PRNP and prion related doppel prnd variation in domestic cattle
PLOS ONE, 2016Co-Authors: Brian W Brunelle, Allison M Ogrady, Eric M Nicholson, Christopher M SeaburyAbstract:Previous investigations aimed at determining whether the mammalian prion protein actually facilitates tangible molecular aspects of either a discrete or pleiotropic functional niche have been debated, especially given the apparent absence of overt behavioral or physiological phenotypes associated with several mammalian prion gene (PRNP) knockout experiments. Moreover, a previous evaluation of PRNP knockout cattle concluded that they were normal, suggesting that the bovine prion protein is physiologically dispensable. Herein, we examined the frequency and distribution of nucleotide sequence variation within the coding regions of bovine PRNP and the adjacent Doppel (PRND) gene, a proximal paralogue to PRNP on BTA13. Evaluation of PRND variation demonstrated that the gene does not depart from a strictly neutral model of molecular evolution, and would therefore not be expected to influence tests of selection within PRNP. Collectively, our analyses confirm that intense purifying selection is indeed occurring directly on bovine PRNP, which is indicative of a protein with an important role. These results suggest that the lack of observed fitness effects may not manifest in the controlled environmental conditions used to care for and raise PRNP knockout animals.
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Molecular Characterization of the Rocky Mountain Elk (Cervus elaphus nelsoni) PRNP Putative Promoter
Journal of Heredity, 2007Co-Authors: Christopher M Seabury, Clare A. Gill, Joe W. Templeton, Joseph B. Dyar, James N. Derr, David L. Adelson, Elaine Owens, Donald S. Davis, Duane C. Kraemer, James E. WomackAbstract:Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) affecting deer (Odocoileus spp.), moose (Alces alces), and Rocky Mountain elk (Cervus elaphus nelsoni). Leucine homozygosity at elk PRNP codon 132 has been associated with reduced CWD susceptibility. However, naturally acquired CWD has been detected in elk possessing the 132 Leu/Leu genotype. Recent human and bovine studies indicate that PRNP regulatory polymorphisms may also influence TSE occurrence. Therefore, we generated sequences for the elk PRNP putative promoter (2.2 kb), exon 1 (predicted; 54 bp), intron 1 (predicted; 193 bp), and exon 3 (771 bp). Promoter prediction analysis using CpGProD yielded a single elk PRNP promoter that was homologous to regions of known promoter activity in cow and sheep. Molecular interrogation of the elk PRNP putative promoter revealed 32 diallelic single-nucleotide polymorphisms (SNPs). No variation was detected within the predicted exon 1 or intron 1 sequences. Evaluation of elk PRNP exon 3 revealed 3 SNPs (63Y, 312R, 394W/Met/Leu). Bayesian haplotype reconstruction resulted in 3 elk PRNP haplotypes, with complete linkage disequilibrium observed between all PRNP putative promoter SNPs and codon 132. The results of this study provide the initial genomic foundation for future comparative and haplotype-based elk PRNP studies.
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prion protein gene PRNP variants and evidence for strong purifying selection in functionally important regions of bovine exon 3
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Christopher M Seabury, Rodney L Honeycutt, Alejandro P Rooney, Natalie D Halbert, James N. DerrAbstract:Amino acid replacements encoded by the prion protein gene (PRNP) have been associated with transmissible and hereditary spongiform encephalopathies in mammalian species. However, an association between bovine spongiform encephalopathy (BSE) and bovine PRNP exon 3 has not been detected. Moreover, little is currently known regarding the mechanisms of evolution influencing the bovine PRNP gene. Therefore, in this study we evaluated the patterns of nucleotide variation associated with PRNP exon 3 for 36 breeds of domestic cattle and representative samples for 10 additional species of Bovinae. The results of our study indicate that strong purifying selection has intensely constrained PRNP over the long-term evolutionary history of the subfamily Bovinae, especially in regions considered to be of functional, structural, and pathogenic importance in humans as well as other mammals. The driving force behind this intense level of purifying selection remains to be explained.
Stanley B Prusiner - One of the best experts on this subject based on the ideXlab platform.
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A novel vector for transgenesis in the rat CNS
Acta Neuropathologica Communications, 2017Co-Authors: T. Peter Lopez, Brittany N. Dugger, Carlo Condello, Zuzana Krejciova, J. Alberto Castañeda, Abby Oehler, Kurt Giles, George A Carlson, Stanley B PrusinerAbstract:The larger brain of the rat enables a much greater repertoire of complex behaviors than mice, likely making rats preferential for investigating neurodegeneration. Because molecular tools for specific expression of transgenes in the rat brain are sparse, we chose PRNP encoding the prion protein (PrP) to develop a novel vector to drive transgene expression in the rat brain. We compared the rat PRNP sequence with mouse and Syrian hamster PRNP sequences, identifying conserved genetic elements and hypothesizing that these elements would be able to drive neuronal transgene expression. We investigated this by generating a vector termed RaPRNP that encompasses portions of the rat PRNP gene. Importantly, we replaced the rat PRNP open reading frame (ORF) with a cloning site for rapid and seamless In-Fusion cloning. To validate the in vivo neuronal specificity of the RaPRNP vector in rats, we generated stable RaPRNP-LacZ/enhanced green fluorescent protein (EGFP) transgenic (Tg) rat lines, which led to robust LacZ activity and high EGFP fluorescence in the central nervous system of embryos and adult animals. Next, we restored the rat PRNP ORF and generated multiple Tg(RaPRNP-PrP) lines, demonstrating that overexpression of PRNP accelerates the onset of scrapie. While the incubation time in wild-type (WT) rats was 175 ± 3 days post inoculation (dpi), one line, Tg2919, overexpressed RaPrPC at 4.4-fold and exhibited a reduced incubation time of 149 ± 2 dpi. The second line, Tg2922, overexpressed RaPrPC at 9.7-fold compared with WT animals and had an incubation time of 112 ± 0 dpi. Tg2922 rats inoculated with rat RML showed extensive vacuolation of the brainstem in contrast to WT and Tg2919 animals in which vacuolation was most prominent in the hippocampus and striatum as well as the motor and sensory cortices. It is possible that construction of Tg rats with modified phenotypes will prove more advantageous than mice for neurodegeneration studies.
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doppel is an n glycosylated glycosylphosphatidylinositol anchored protein expression in testis and ectopic production in the brains ofPRNP 0 0 mice predisposed to purkinje cell loss
Journal of Biological Chemistry, 2000Co-Authors: Gregory L Silverman, Stanley B Prusiner, Richard C Moore, Peter Mastrangelo, Ying Yang, Patrick Tremblay, Fred E Cohen, D WestawayAbstract:Abstract The Prnd gene encodes a homolog of the cellular prion protein (PrPC) called doppel (Dpl). Up-regulation of Prnd mRNA in two distinct lines of PrP gene ablated (PRNP 0/0) mice, designatedRcm0 and Ngsk, is associated with death of Purkinje cells. Using recombinant Dpl expressed in Escherichia coli and mouse neuroblastoma cells we demonstrate that wild type (wt) Dpl, like PrPC, adopts a predominantly α-helical conformation, forms intramolecular disulfide bonds, has twoN-linked oligosaccharides, and is presented on the cell surface via a glycosylphosphatidylinositol anchor. Dpl protein was detected in testis of wt mice. Using Triton X-114 phase partitioning to enrich for glycosylphosphatidylinositol-anchored proteins, Dpl was detected in brain samples from Rcm0 PRNP 0/0mice but was absent in equivalent samples from wt mice and ZrchI PRNP 0/0 mice, indicating that ectopic expression of this protein may cause cerebellar pathology in Rcm0 mice. Biochemical and structural similarities between PrPC and Dpl documented here parallel the observation that ataxic Ngsk PRNP 0/0 mice can be rescued by overexpression of wild-type PrP transgenes, and suggest that cell surface PrPC can antagonize the toxic effect of Dpl expressed in the central nervous system.
