Search Results (25)

Chronic wasting disease (CWD) is a prion disease of cervids marked by growing strain diversity and variation in host susceptibility. Central to this complexity are prion protein gene (Prnp) polymorphisms, which can modulate pathogenesis by altering the ability of cellular prion protein (PrP^C) to misfold into infectious prions (PrP^Sc), or by promoting the emergence of novel strains. Studies in cervids and transgenic rodent models demonstrate that individual polymorphisms influence PrP stability, conversion efficiency, and the selection of PrP^Sc conformers, with most variants conferring partial resistance but none offering complete protection. These host–strain interactions define transmission barriers and disease phenotype. Understanding how Prnp genotypes shape CWD strain diversity is essential for predicting transmission dynamics, refining surveillance, and assessing zoonotic potential as the disease continues to expand geographically and genetically. Full article

Scrapie (classical and atypical) susceptibility in sheep is strongly influenced by PRNP gene polymorphisms. In Portugal, limited data exist for native breeds such as Serra da Estrela, despite their relevance to animal conservation and food production. The full coding region of PRNP gene of 92 Serra da Estrela sheep was sequenced and SNP frequencies were analysed. The predicted functional impact of nonsynonymous SNPs was assessed using PolyPhen-2 and AMYCO. A total of 27 SNPs were identified, including 20 nonsynonymous variants. Thirteen major haplotypes were observed. The ARR allele, which provides resistance to classical scrapie, was present in 58.7% of the population, with 18.5% of animals being homozygous. Several previously unreported SNPs were identified, and their impact on prion protein aggregation propensity and structure was explored. The high frequency of the ARR allele without full ARR fixation suggests that no selective breeding for scrapie resistance has been applied. These results support the adoption of gradual selection strategies that preserve genetic variability and promote farmer compliance, while increasing classical and atypical scrapie resistance. Full article

Prion diseases are fatal neurological disorders characterized by abnormal protein accumulation in the brain, leading to neurodegeneration, dementia, and ataxia. Sporadic Creutzfeldt–Jakob disease (sCJD), the most common form, accounts for 80–90% of cases and progresses rapidly, with most patients surviving <6 months to a year after symptom onset, indicating the importance of early diagnosis. The disease is classified into six subtypes based on PRNP gene polymorphisms, with differences in protein degradation patterns contributing to the diversity of clinical symptoms. However, diagnosis remains challenging because of the variability in clinical presentation and disease duration. Traditional diagnostic criteria established by the World Health Organization (WHO) rely on clinical findings, electroencephalogram, and cerebrospinal fluid tests, such as the 14-3-3 protein assay. However, these criteria require pathological confirmation, often delaying diagnosis. The recently proposed Hermann’s criteria represent a significant advancement by incorporating newer biomarkers, including magnetic resonance imaging, real-time quaking-induced conversion assay, tau protein, and neurofilament light chain. These criteria improve diagnostic sensitivity and specificity but have a slightly higher risk of false positives. This review compares the effectiveness of these biomarkers with the WHO criteria and highlights the importance of early diagnosis for improving patient care. Full article

Prion diseases are fatal neurodegenerative diseases that can be transmitted by infectious protein particles, PrP^Scs, encoded by the endogenous prion protein gene (PRNP). The origin of prion seeds is unclear, especially in non-human hosts, and this identification is pivotal to preventing the spread of prion diseases from host animals. Recently, an abnormally high amyloid propensity in prion proteins (PrPs) was found in a frog, of which the genetic variations in the PRNP gene have not been investigated. In this study, genetic polymorphisms in the PRNP gene were investigated in 194 Dybowski’s frogs using polymerase chain reaction (PCR) and amplicon sequencing. We carried out in silico analyses to predict functional alterations according to non-synonymous single nucleotide polymorphisms (SNPs) using PolyPhen-2, PANTHER, SIFT, and MutPred2. We used ClustalW2 and MEGA X to compare frog PRNP and PrP sequences with those of prion-related animals. To evaluate the impact of the SNPs on protein aggregation propensity and 3D structure, we utilized AMYCO and ColabFold. We identified 34 novel genetic polymorphisms including 6 non-synonymous SNPs in the frog PRNP gene. The hydrogen bond length varied at codons 143 and 207 according to non-synonymous SNPs, even if the electrostatic potential was not changed. In silico analysis predicted S143N to increase the aggregation propensity, and W6L, C8Y, R211W, and L241F had damaging effects on frog PrPs. The PRNP and PrP sequences of frogs showed low homology with those of prion-related mammals. To the best of our knowledge, this study was the first to discover genetic polymorphisms in the PRNP gene in amphibians. Full article

Prion diseases are fatal neurodegenerative disorders caused by the misfolding of the normal cellular prion protein (PrP^C) into its infectious isoform (PrP^Sc). Although prion diseases in humans, sheep, goats, and cattle have been extensively studied, feline spongiform encephalopathy (FSE) remains poorly understood. Genetic factors, particularly polymorphisms in the prion protein gene (PRNP) and prion-like protein gene (PRND), have been linked to prion disease susceptibility in various species. However, no studies have yet investigated the PRND gene in cats with respect to prion diseases. Therefore, we investigated polymorphisms in the feline PRND gene and analyzed their genetic characteristics. We sequenced the coding region of the PRND gene using samples from 210 domestic cats and determined the genotype and allele frequencies of PRND polymorphisms. We identified thirteen novel single nucleotide polymorphisms (SNPs), including six non-synonymous variants and one insertion/deletion (InDel) in the feline PRND gene. Four of the non-synonymous SNPs were predicted to have deleterious effects on the Doppel protein’s structure and function. Notably, the SNP c.97A>G (I33V) showed potential structural clashes, and the others formed additional hydrogen bonds. The LD analysis revealed strong genetic associations between the PRND SNPs and the PRNP InDel, suggesting linkage between these loci in cats. This study identifies novel PRND polymorphisms in domestic cats and provides new insights into the genetic factors underlying feline susceptibility to prion diseases. The strong genetic linkage between PRND and PRNP polymorphisms, coupled with predictions of detrimental effects on Doppel protein structure, suggests that PRND gene variants could influence prion disease progression in cats. These findings provide a foundational framework for future studies on the functional implications of PRND polymorphisms in FSE. To the best of our knowledge, this study is the first report on the genetic characteristics of PRND polymorphisms in cats. Full article

Prion diseases are neurodegenerative disorders caused by misfolded prion proteins. Although rare, the said diseases are always fatal; they commonly cause death within months of developing clinical symptoms, and their diagnosis is exceptionally difficult pre-mortem. There are no known cures or treatments other than symptomatic care. Given the aggressiveness of prion diseases on onset, therapies after disease onset could be challenging. Prevention to reduce the incidence or to delay the disease onset has been suggested to be a more feasible approach. In this perspective article, we summarize our current understandings of the origin, risk factors, and clinical manifestations of prion diseases. We propose a PCR testing of the blood to identify PRNP gene polymorphisms at codons 129 and 127 in individuals with familial PRNP mutations to assess the risk. We further present the CRISPR/Cas9 gene editing strategy as a perspective preventative approach for these high-risk individuals to induce a polymorphic change at codon 127 of the PRNP gene, granting immunity to prion diseases in selected high-risk individuals, in particular, in individuals with familial PRNP mutations. Full article

Prion disorders are fatal infectious diseases that are caused by a buildup of pathogenic prion protein (PrP^Sc) in susceptible mammals. According to new findings, the shadow of prion protein (Sho) encoded by the shadow of prion protein gene (SPRN) is associated with prion protein (PrP), promoting the progression of prion diseases. Although genetic polymorphisms in SPRN are associated with susceptibility to several prion diseases, genetic polymorphisms in the rabbit SPRN gene have not been investigated in depth. We discovered two novel single nucleotide polymorphisms (SNPs) in the leporine SPRN gene on chromosome 18 and found strong linkage disequilibrium (LD) between them. Additionally, strong LD was not found between the polymorphisms of PRNP and SPRN genes in rabbits. Furthermore, nonsynonymous SNPs that alter the amino acid sequences within the open reading frame (ORF) of SPRN have been observed in prion disease-susceptible animals, but this is the first report in rabbits. As far as we are aware, this study represents the first examination of the genetic features of the rabbit SPRN gene. Full article

Bovine spongiform encephalopathy (BSE) is a fatal disease in cattle caused by misfolded prion proteins and linked to indel polymorphisms in the promoter and intron 1 of the PRNP gene. The aim of this study was to determine the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms and to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels via polymerase chain reaction (PCR) in Zhongdian Yak (Bos-grunniens) (YK), Zhongdian Yellow cattle (Bos-taurus) (YC), and Zhongdian Yakow (Bos-primigenius taurus × Bos-grunniens) (PK). Resultant high allelic frequencies were found in 23− and 12+, while haplotype frequencies were very low in 23+/12 in YK, YC, and PK. PRNP expression was higher in the +−/−− diplotype of the PK and (mean ± SE) was 3.6578 ± 1.85964. Furthermore, two variable sites were investigated—a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site. Additionally, reporter gene assays revealed a link between two proposed transcription factors and lower expression levels of the +/+ allele compared with the −/− allele. The expression level of PRNP was shown to be dependent on two indel polymorphisms in the bovine PRNP promoter, which includes binding sites for RP58 and SP1 transcription factors. These findings raised the possibility that the PRNP genotype may contribute to the high variation in PRNP expression. Full article

Scrapie is a fatal, neurodegenerative disease that affects sheep and goats, and genetic susceptibility to scrapie in sheep is associated with polymorphisms in the prion protein (PRNP) gene. The aim of this study is to identify PRNP polymorphism in Awassi sheep from Türkiye, the Palestinian Authority, and Saudi Arabia. A total of 150 healthy sheep were genotyped for PRNP, using Sanger sequencing. There were seven alleles and eleven genotypes observed based on codons 136, 154, and 171 of PRNP. The ARQ allele was predominant in all populations. The most resistant allele to scrapie, ARR, was present in all three regions. The VRQ allele, associated with the highest susceptibility to scrapie, was detected only in Türkiye at a low frequency. In this study, twenty-seven amino acid substitutions were found. Eight of them (R40Q, G65E, H88L, S98T, A118P, S138T, V192F and L250I) have not been previously reported. These data indicate that sheep breeds close to the sheep domestication center have maintained high genetic diversity in the PRNP region. Our findings on PRNP will provide valuable insights for sheep breeding programs, aiding in the selection of genotypes resistant to scrapie in Türkiye, the Palestinian Authority, and Saudi Arabia. Full article

Background: The variability of prion protein gene (PRNP) codons and the frequency of alleles (K222, D146, and S146) that appear to confer genetic resistance to classical scrapie are still unknown in several goat populations/breeds prevalent in Romania. This work aims to assess the genetic polymorphism at 15 PRNP codons in Romanian goat populations to inform the development of goat breeding programs for scrapie resistance. Methods: Whole blood and hair follicles from Carpathian (50), French Alpine (53), and Banat’s White (53) breed goats were sampled to extract genomic DNA for genetic analyses and Sanger sequencing. In the targeted goat groups, one classical scrapie-positive Banat’s White goat was included. Results: The codons without polymorphisms were G37G, W102W, N146N, R151R, S173S, and I218I. The following non-synonymous polymorphisms of PRNP were recorded: P110P, P110S, P110T, T110T, G127G, G127S, I142I, I142M, T142I, H143H, P143P, R143R, R154R, H154R, P168P, Q168Q, Q211Q, Q211R, Q222Q, H222Q, K222K, S240S, P240P, P240S, and S240P. Conclusions: PRNP polymorphism was recorded in 60% (9/15) of codons. The scrapie-positive Banat’s White goat had G37G, W102W, T110T, G127G, I142I, H143H, N146N, R151R, R154R, P168P, S173S, R211R, I218I, Q222Q, and S240S. The K222 allele had a frequency of 6% (3/50) in Carpathian, 9.43% (5/53) in Banat’s White, and 15.09% (8/53) in French Alpine. Therefore, the polymorphisms detected in this sample of Romanian goat breeds are too rare to design a breeding program at the current time. Full article

Background and Objectives: Prion diseases are fatal neurodegenerative disorders caused by the abnormal proteinase K-resistant prion protein (PrP^Sc). Since variant Creutzfeldt–Jakob disease (CJD) was first reported in the United Kingdom (UK) in 1996, the occurrence of variant CJD has been reported in over 10 countries. To date, variant CJD has not been reported in Korea. However, the E211K somatic mutation in the prion protein gene (PRNP), which is related to bovine spongiform encephalopathy (BSE), was reported in Korean Holstein cattle, and atypical BSE, which is supposed to be sporadic BSE, has been occurring in many countries, including Japan and the USA. These results suggest that BSE may occur naturally in Korea. Thus, we performed a preemptive PrP^Sc test in appendix specimens to diagnose variant CJD in a Korean population. Materials and Methods: In the present study, we investigated CJD-related mutations and polymorphisms of the PRNP gene and carried out an examination on PrP^Sc in appendix specimens of Korean patients after appendectomy. Results: In all Korean appendix specimens tested, PrP^Sc bands were not detected. Conclusion: To the best of our knowledge, this was the first evaluation of PrP^Sc in Korean appendix specimens. Full article

Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by pathogenic prion protein (PrP^Sc) originating from normal prion protein (PrP^C) and have been reported in several types of livestock and pets. Recent studies have reported that the shadow of prion protein (Sho) encoded by the shadow of prion protein gene (SPRN) interacts with prion protein (PrP) and accelerates prion diseases. In addition, genetic polymorphisms in the SPRN gene are related to susceptibility to prion diseases. However, genetic polymorphisms in the feline SPRN gene and structural characteristics of the Sho have not been investigated in cats, a major host of feline spongiform encephalopathy (FSE). We performed amplicon sequencing to identify feline SPRN polymorphisms in the 623 bp encompassing the open reading frame (ORF) and a small part of the 3′ untranslated region (UTR) of the SPRN gene. We analyzed the impact of feline SPRN polymorphisms on the secondary structure of SPRN mRNA using RNAsnp. In addition, to find feline-specific amino acids, we carried out multiple sequence alignments using ClustalW. Furthermore, we analyzed the N-terminal signal peptide and glycosylphosphatidylinositol (GPI)-anchor using SignalP and PredGPI, respectively. We identified three novel SNPs in the feline SPRN gene and did not find strong linkage disequilibrium (LD) among the three SNPs. We found four major haplotypes of the SPRN polymorphisms. Strong LD was not observed between PRNP and SPRN polymorphisms. In addition, we found alterations in the secondary structure and minimum free energy of the mRNA according to the haplotypes in the SPRN polymorphisms. Furthermore, we found four feline-specific amino acids in the feline Sho using multiple sequence alignments among several species. Lastly, the N-terminal signal sequence and cutting site of the Sho protein of cats showed similarity with those of other species. However, the feline Sho protein exhibited the shortest signal sequence and a unique amino acid in the omega-site of the GPI anchor. To the best of our knowledge, this is the first report on genetic polymorphisms of the feline SPRN gene. Full article

Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (PRNP). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the PRNP codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrP^Sc), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrP^Sc profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV). Full article

Prion diseases are fatal, chronic, and incurable neurodegenerative diseases caused by pathogenic forms of prion protein (PrP^Sc) derived from endogenous forms of prion protein (PrP^C). Several case–control and genome-wide association studies have reported that the M129V polymorphism of the human prion protein gene (PRNP) is significantly associated with susceptibility to sporadic Creutzfeldt–Jakob disease (CJD). However, since some case–control studies have not shown these associations, the results remain controversial. We collected data that contain the genotype and allele frequencies of the M129V single-nucleotide polymorphism (SNP) of the PRNP gene and information on ethnic backgrounds from sporadic CJD patients. We performed a meta-analysis by collecting data from eligible studies to evaluate the association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD. We found a very strong association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD using a meta-analysis for the first time. We validated the eligibility of existing reports and found severe heterogeneity in some previous studies. We also found that the MM homozygote is a potent risk factor for sporadic CJD compared to the MV heterozygote in the heterozygote comparison model (MM vs. MV, odds ratio = 4.9611, 95% confidence interval: 3.4785; 7.0758, p < 1 × 10⁻¹⁰). To the best of our knowledge, this was the first meta-analysis assessment of the relationship between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD. Full article

Scrapie is considered an endemic disease in both sheep and goats in Greece. However, contrary to sheep, in goats more than one prion protein (PrP) polymorphism has been recognized as a candidate for resistance breeding against the disease. For an impression, candidates which are circulating, (i) brain samples (n = 525) from scrapie-affected (n = 282) and non-affected (n = 243) animals within the national surveillance program, and (ii) individual blood samples (n = 1708) from affected (n = 241) and non-affected (n = 1467) herds, in a large part of mainland Greece and its islands, were collected and assayed. A dedicated Taqman method was used to test for amino acid polymorphisms 110T/P, 146N/S/D, 211R/Q, and 222Q/K. Highly prevalent genotypes were 110TT, 146NN, 211RR, and 222QQ. The frequencies of polymorphisms in blood and negative brain samples for codons 110P, 211Q, and 222K were 4.0%, 3.0%, and 1.9%, respectively, while 146D (0.7%) was present only on Karpathos island. Codon 110P was exclusively found in scrapie-negative brains, and homozygous 110P/P in two scrapie-negative goats. It is concluded that breeding programs in Karpathos could focus on codon 146D, while in other regions carriers of the 110P and 222K allele should be sought. Case-control and challenge studies are now necessary to elucidate the most efficient breeding strategies. Full article