Scrapie susceptibility-associated indel polymorphism of shadow of prion protein gene (SPRN) in Korean native black goats

Abstract Prion diseases in sheep and goats are called scrapie and belong to a group of transmissible spongiform encephalopathies (TSEs) caused by the abnormal misfolding of the prion protein encoded by the prion protein gene (PRNP). The shadow of the prion protein gene (SPRN) is the only prion gene family member that shows a protein expression profile similar to that of the PRNP gene in the central nervous system. In addition, genetic susceptibility of the SPRN gene has been reported in variant Creutzfeldt–Jakob disease (CJD), bovine spongiform encephalopathy (BSE) and scrapie. However, genetic studies of the SPRN gene have not been carried out in Korean native black goats. Here, we investigated the genotype and allele frequencies of SPRN polymorphisms in 213 Korean native black goats and compared these polymorphisms with those previously reported for scrapie-affected animals. We found a total of 6 polymorphisms including 1 nonsynonymous single nucleotide polymorphism (SNP) and 1 synonymous SNP in the open reading frame (ORF) region and 3 SNPs and 1 indel polymorphism (c.495_496insCTCCC) in the 3′ untranslated region (UTR) by direct DNA sequencing. A significant difference in the allele frequency of the c.495_496insCTCCC indel polymorphism was found between the Italian scrapie-affected goats and the Korean native black goats (P < 0.001). Furthermore, there was a significant difference in the allele frequencies of the c.495_496insCTCCC indel polymorphism between Italian healthy goats and Korean native black goats (P < 0.001). To evaluate the biological impact of the novel nonsynonymous SNP c.416G > A (Arg139Gln), we carried out PROVEAN analysis. PROVEAN predicted the SNP as ‘Neutral’ with a score of −0.297. To the best of our knowledge, this is the first genetic study of the SPRN gene in Korean native black goats.

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Low frequency of the scrapie resistance-associated allele and presence of lysine-171 allele of the prion protein gene in Italian Biellese ovine breed

Journal of General Virology ◽

10.1099/vir.0.80053-0 ◽

2004 ◽

Vol 85 (10) ◽

pp. 3165-3172 ◽

Cited By ~ 31

Author(s):

P. L. Acutis ◽

L. Sbaiz ◽

F. Verburg ◽

M. V. Riina ◽

G. Ru ◽

...

Keyword(s):

Statistical Analysis ◽

Prion Protein ◽

Negative Selection ◽

Protein Gene ◽

Low Frequency ◽

Allele Frequencies ◽

Transmissible Spongiform Encephalopathies ◽

Prion Protein Gene ◽

Spongiform Encephalopathies ◽

Total Frequency

Frequencies of polymorphisms at codons 136, 154 and 171 of the prion protein (PrP) gene were studied in 1207 pure-bred and cross-bred Italian Biellese rams, a small ovine breed of about 65 000 head in Italy. Aside from the five most common alleles (VRQ, ARQ, ARR, AHQ and ARH), the rare ARK allele was also found, with the highest frequency reported so far in an ovine breed (2·5 %). ARK/--- genotypes had a total frequency of 4·9 %. The resistance-associated ARR allele was seen at a low frequency (8·3 %). Only 1·4 % of animals examined had a resistant ARR/ARR PrP genotype. Semi-resistant (ARR/ARQ, ARR/ARH and ARR/AHQ) PrP genotypes had a total frequency of 12·6 % and PrP genotypes that are associated with high scrapie susceptibility (e.g. VRQ/VRQ and ARQ/ARQ) had a total frequency of 81·1 %. Statistical analysis comparing PrP allele frequencies between pure-bred and cross-bred animals showed that the ARR allele occurred at a significantly lower frequency in pure-bred rams. Furthermore, comparison of PrP allele frequencies between pure-bred rams over 18 months of age and those below 18 months of age showed a significant decrease in the ARR allele in breeding rams over 18 months of age. Based on these results, breeding for scrapie resistance in the Biellese breed will have to take into account the low frequency of the ARR allele, which also seems to be subject to negative selection by farmers. Further investigation is required to understand whether the ARK allele is also associated with resistance to transmissible spongiform encephalopathies.

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Genotype distribution of the prion protein gene (PRNP) promoter polymorphisms in Korean cattle

Genome ◽

10.1139/g06-110 ◽

2006 ◽

Vol 49 (12) ◽

pp. 1539-1544 ◽

Cited By ~ 24

Author(s):

Byung-Hoon Jeong ◽

Yun-Jung Lee ◽

Nam-Ho Kim ◽

R.I. Carp ◽

Yong-Sun Kim

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Spongiform Encephalopathy ◽

Holstein Cattle ◽

Genotype Distribution ◽

Prion Protein Gene ◽

Indel Polymorphism ◽

Promoter Polymorphisms ◽

Hanwoo Cattle ◽

German Cattle

Recently, an association between bovine spongiform encephalopathy (BSE) and insertion/deletion (indel) polymorphisms in the bovine prion protein gene (PRNP) promoter region has been reported in German cattle. These PRNP polymorphisms cause changes in PRNP expression and are thought to play an important role in BSE susceptibility. BSE has been reported in British and Japanese Holstein cattle but has not been diagnosed in Hanwoo cattle (Bos taurus coreanae) up to now. These results prompted us to investigate the genotype distributions of these PRNP promoter polymorphisms in 107 Hanwoo cattle and 52 Holstein cattle and compare the results with those of previous studies. A significant difference (P = 0.0249) in allele frequency of the 23 bp indel polymorphism was observed between Hanwoo and the BSE-affected German cattle previously investigated. There were no significant differences in the genotype (P = 0.2095) or allele (P = 0.8875) frequencies of the 12 bp indel polymorphism between Hanwoo and BSE-affected German cattle. Interestingly, the genotype and allele frequencies of the 23 bp indel polymorphism in Korean Holsteins were very similar to those previously reported for BSE-affected German cattle and healthy US cattle sires.

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Functional disruption of the prion protein gene in cloned goats

Journal of General Virology ◽

10.1099/vir.0.81384-0 ◽

2006 ◽

Vol 87 (4) ◽

pp. 1019-1027 ◽

Cited By ~ 41

Author(s):

Guohua Yu ◽

Jianquan Chen ◽

Huiqing Yu ◽

Siguo Liu ◽

Juan Chen ◽

...

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Cellular Prion Protein ◽

Abnormal Development ◽

Transmissible Spongiform Encephalopathies ◽

Membrane Glycoprotein ◽

Prion Protein Gene ◽

Spongiform Encephalopathies ◽

Scrapie Infection ◽

Large Animals

The cellular prion protein (PrPC), a membrane glycoprotein anchored to the outer surface of neurons, lymphocytes and other cells, is associated directly with the pathogenesis of the transmissible spongiform encephalopathies (TSEs) occurring mainly in humans, cattle, sheep and goats. Although mice lacking PrPC develop and reproduce normally and are resistant to scrapie infection, large animals lacking PrPC, especially those species in which TSE occurs naturally, are currently not available. Here, five live PRNP +/− goats cloned by gene targeting are reported. Detailed RNA-transcription and protein-expression analysis of one PRNP +/− goat showed that one allele of the caprine PRNP gene had been disrupted functionally. No gross abnormal development or behaviour could be seen in these PRNP +/− goats up to at least 3 months of age. These heterozygous PRNP +/− goats are ready to be used in producing homozygous PRNP −/− goats in which no PrPC should be expressed.

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Genetic Variation in the Prion Protein Gene (PRNP) of Two Tunisian Goat Populations

Animals ◽

10.3390/ani11061635 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1635

Author(s):

Samia Kdidi ◽

Mohamed Habib Yahyaoui ◽

Michela Conte ◽

Barbara Chiappini ◽

Mohamed Hammadi ◽

...

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Transmissible Spongiform Encephalopathies ◽

Prion Protein Gene ◽

Breeding Programs ◽

Low Frequencies ◽

Spongiform Encephalopathies ◽

Prolonged Incubation ◽

Global View ◽

First Time

Scrapie is a fatal prion disease. It belongs to transmissible spongiform encephalopathies (TSEs), and occurs in sheep and goats. Similarly, to ovine species, the prion protein gene (PRNP) plays a major role in conferring resistance or susceptibility to TSE in goats. This study assesses the variability of PRNP in native and crossed-breed goat populations raised in the Southeast of Tunisia and provides information on the distribution of PRNP haplotypes and genotypes in these goat populations. A total of 116 unrelated goats including 82 native and 34 crossed-breed goats were screened for PRNP polymorphisms using Sanger sequencing. Sequence analysis revealed 10 non-synonymous polymorphisms (G37V, M137I, R139S, I142M, H143R, N146D, R154H, R211Q, Q222K, and S240P), giving rise to 12 haplotypes and 23 genotypes. Moreover, four silent mutations were detected at codons 30, 42, 138, and 179; the former was reported for the first time in goat (nucleotide 60 c→t). Interestingly, the PrP variants associated with resistance (D146 and K222) or with a prolonged incubation time of goat to scrapie (M142, R143, H154, Q211) were absent or detected with low frequencies except for H154 variant, which is present with high frequency (1%, 1%, 4%, 0%, 88%, and 6%, respectively, for native goats, and 0%, 1%, 0%, 1%, 78%, and 1%, respectively, for crossed goats). The analysis of PRNP polymorphisms of goats raised in other regions of the country will be useful in getting a global view of PRNP genetic variability and the feasibility of goat breeding programs in Tunisia.

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Evolution of Transmissible Spongiform Encephalopathies and the Prion Protein Gene (PRNP) in Mammals

Journal of Mammalian Evolution ◽

10.1007/s10914-021-09557-6 ◽

2021 ◽

Author(s):

Brittaney L. Buchanan ◽

Robert M. Zink

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Transmissible Spongiform Encephalopathies ◽

Prion Protein Gene ◽

Spongiform Encephalopathies

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Prion protein gene (PRNP) polymorphisms in native Chinese cattle

Genome ◽

10.1139/g09-087 ◽

2010 ◽

Vol 53 (2) ◽

pp. 138-145 ◽

Cited By ~ 14

Author(s):

Hui Zhao ◽

Xiao-Yan Wang ◽

Wei Zou ◽

Ya-Ping Zhang

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Southern China ◽

Spongiform Encephalopathy ◽

Prion Protein Gene ◽

Coding Region ◽

Low Frequencies ◽

Frequency Distributions ◽

Chinese Cattle ◽

Significant Difference

Polymorphisms in four regions of the bovine prion protein gene (PRNP) confer susceptibility to bovine spongiform encephalopathy (BSE). These polymorphisms include a 23-bp insertion/deletion (indel) in the promoter region, a 12-bp indel in intron 1, an octapeptide repeat or 24-bp indel in the open reading frame, and a single nucleotide polymorphism (SNP) in the coding region. In this study, we investigated the frequency distributions of genotypes, alleles, and haplotypes at these indel sites in 349 native Chinese cattle and sequence variants in 50 samples. Our results showed that cattle in southern China have low frequencies of the 12-bp deletion allele and the 23-bp deletion / 12-bp deletion haplotype, which have been suggested to be relevant to BSE susceptibility. Interestingly, a significant difference was observed between BSE-affected cattle and healthy Chinese cattle in the 12-bp indel polymorphism. A total of 14 SNPs were discovered in the coding region of PRNP in Chinese cattle. Three of these SNPs were associated with amino acid changes (K3T, P54S, and S154N). The E211K substitution that was recently reported in the US atypical BSE case was not detected in this study.

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PRION PROTEIN GENE SEQUENCES ANALYSIS IN TWELVE SHEEP BREEDS OF PAKISTAN

AGROFOR ◽

10.7251/agreng1902057f ◽

2021 ◽

Vol 4 (2) ◽

Author(s):

Mohammad Farooque HASSAN

Keyword(s):

Sequence Analysis ◽

Prion Protein ◽

Protein Gene ◽

Mammalian Species ◽

Pcr Amplification ◽

Transmissible Spongiform Encephalopathies ◽

Prion Protein Gene ◽

Spongiform Encephalopathies ◽

Sheep Breeds ◽

Abnormal Form

Prions are considered the only agents of transmissible spongiform encephalopathies (TSEs) and are harmful pathogens of mammals. These infectious agents of host are made up through aggregation of conformational isomers (PrPSc) and encode glycoprotein (PrPC) of 33-35 kDa. TSEs are the fatal group of diseases which are neurodegenerative and include chronic wasting disease in deer and elk, Creutzfeldt-Jakob disease (CJD) and transmissible mink encephalopathy (TME) in humans and scrapie in goats and sheep. The accumulation of abnormal form of the normal protein (PrP) is common in all diseases related TSE. This abnormal form of PrP called PrPSc is resistant to proteolysis as well as infectious. Present study was conducted in order to do sequence analysis of prion protein gene in twelve breeds of the sheep. We studied this gene to elucidate 12 of Pakistani sheep breeds and to compare gene order with other mammalian species. PCR amplification of 771 bp fragment was done on selected samples from all twelve breeds followed by sequencing. Sequence analysis was done and some sites were found to be heterozygous. These findings on prion protein gene in sheep will provide assistance for further studies on pathogenesis, cross-species transmission, breeding programs, resistance and susceptibility to scrapie.

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Novel Polymorphisms and Genetic Characteristics of the Prion Protein Gene (PRNP) in Dogs—A Resistant Animal of Prion Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21114160 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4160 ◽

Cited By ~ 1

Author(s):

Dong-Ju Kim ◽

Yong-Chan Kim ◽

An-Dang Kim ◽

Byung-Hoon Jeong

Keyword(s):

Hydrogen Bonds ◽

Prion Protein ◽

Protein Gene ◽

Direct Sequencing ◽

Transmissible Spongiform Encephalopathies ◽

Prion Protein Gene ◽

Genetic Characteristics ◽

Aggregation Propensity ◽

Wide Range ◽

The Impact

Transmissible spongiform encephalopathies (TSEs) have been reported in a wide range of species. However, TSE infection in natural cases has never been reported in dogs. Previous studies have reported that polymorphisms of the prion protein gene (PRNP) have a direct impact on the susceptibility of TSE. However, studies on polymorphisms of the canine PRNP gene are very rare in dogs. We examined the genotype, allele, and haplotype frequencies of canine PRNP in 204 dogs using direct sequencing and analyzed linkage disequilibrium (LD) using Haploview version 4.2. In addition, to evaluate the impact of nonsynonymous polymorphisms on the function of prion protein (PrP), we carried out in silico analysis using PolyPhen-2, PROVEAN, and PANTHER. Furthermore, we analyzed the structure of PrP and hydrogen bonds according to alleles of nonsynonymous single nucleotide polymorphisms (SNPs) using the Swiss-Pdb Viewer program. Finally, we predicted the impact of the polymorphisms on the aggregation propensity of dog PrP using AMYCO. We identified a total of eight polymorphisms, including five novel SNPs and one insertion/deletion polymorphism, and found strong LDs and six major haplotypes among eight polymorphisms. In addition, we identified significantly different distribution of haplotypes among eight dog breeds, however, the kinds of identified polymorphisms were different among each dog breed. We predicted that p.64_71del HGGGWGQP, Asp182Gly, and Asp182Glu polymorphisms can impact the function and/or structure of dog PrP. Furthermore, the number of hydrogen bonds of dog PrP with the Glu182 and Gly182 alleles were predicted to be less than those with the Asp182 allele. Finally, Asp163Glu and Asp182Gly showed more aggregation propensity than wild-type dog PrP. These results suggest that nonsynonymous SNPs, Asp182Glu and Asp182Gly, can influence the stability of dog PrP and confer the possibility of TSE infection in dogs.

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First Report of the Potential Bovine Spongiform Encephalopathy (BSE)-Related Somatic Mutation E211K of the Prion Protein Gene (PRNP) in Cattle

International Journal of Molecular Sciences ◽

10.3390/ijms21124246 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4246 ◽

Cited By ~ 2

Author(s):

Sae-Young Won ◽

Yong-Chan Kim ◽

Byung-Hoon Jeong

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Somatic Mutation ◽

Prion Disease ◽

In Silico ◽

Somatic Mutations ◽

Protein Gene ◽

Prnp Gene ◽

Spongiform Encephalopathy ◽

Prion Protein Gene

Bovine spongiform encephalopathy (BSE) is a prion disease characterized by spongiform degeneration and astrocytosis in the brain. Unlike classical BSE, which is caused by prion-disease-contaminated meat and bone meal, the cause of atypical BSE has not been determined. Since previous studies have reported that the somatic mutation in the human prion protein gene (PRNP) has been linked to human prion disease, the somatic mutation of the PRNP gene was presumed to be one cause of prion disease. However, to the best of our knowledge, the somatic mutation of this gene in cattle has not been investigated to date. We investigated somatic mutations in a total of 58 samples, including peripheral blood; brain tissue including the medulla oblongata, cerebellum, cortex, and thalamus; and skin tissue in 20 individuals from each breed using pyrosequencing. In addition, we estimated the deleterious effect of the K211 somatic mutation on bovine prion protein by in silico evaluation tools, including PolyPhen-2 and PANTHER. We found a high rate of K211 somatic mutations of the bovine PRNP gene in the medulla oblongata of three Holsteins (10% ± 4.4%, 28% ± 2%, and 19.55% ± 3.1%). In addition, in silico programs showed that the K211 somatic mutation was damaging. To the best of our knowledge, this study is the first to investigate K211 somatic mutations of the bovine PRNP gene that are associated with potential BSE progression.

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