The First Report of the Prion Protein Gene (PRNP) Sequence in Pekin Ducks (Anas platyrhynchos domestica): The Potential Prion Disease Susceptibility in Ducks

Pathogenic prion protein (PrPSc), converted from normal prion protein (PrPC), causes prion disease. Although prion disease has been reported in several mammalian species, chickens are known to show strong resistance to prion diseases. In addition to chickens, the domestic duck occupies a large proportion in the poultry industry and may be regarded as a potential resistant host against prion disease. However, the DNA sequence of the prion protein gene (PRNP) has not been reported in domestic ducks. Here, we performed amplicon sequencing targeting the duck PRNP gene with the genomic DNA of Pekin ducks. In addition, we aligned the PrP sequence of the Pekin duck with that of various species using ClustalW2 and carried out phylogenetic analysis using Molecular Evolutionary Genetics Analysis X (MEGA X). We also constructed the structural modeling of the tertiary and secondary structures in avian PrP using SWISS-MODEL. Last, we investigated the aggregation propensity on Pekin duck PrP using AMYCO. We first reported the DNA sequence of the PRNP gene in Pekin ducks and found that the PrP sequence of Pekin ducks is more similar to that of geese than to that of chickens and mallards (wild ducks). Interestingly, Pekin duck PrP showed a high proportion of β-sheets compared to that of chicken PrP, and a high aggregation propensity compared to that of avian PrPs. However, Pekin duck PrP with substitutions of chicken-specific amino acids showed reduced aggregation propensities. To the best of our knowledge, this is the first report on the genetic characteristics of the PRNP sequence in Pekin ducks.

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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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Novel Polymorphisms and Genetic Features of the Prion Protein Gene (PRNP) in Cats, Hosts of Feline Spongiform Encephalopathy

Genes ◽

10.3390/genes12010013 ◽

2020 ◽

Vol 12 (1) ◽

pp. 13

Author(s):

Hyeon-Ho Kim ◽

Yong-Chan Kim ◽

Kiwon Kim ◽

An-Dang Kim ◽

Byung-Hoon Jeong

Keyword(s):

Genetic Polymorphisms ◽

Prion Protein ◽

Structural Stability ◽

Prion Disease ◽

Protein Gene ◽

Structural Characteristics ◽

Prion Diseases ◽

Prnp Gene ◽

Spongiform Encephalopathy ◽

Prion Protein Gene

Prion diseases are fatal neurodegenerative disorders characterized by vacuolation and gliosis in the brain. Prion diseases have been reported in several mammals, and genetic polymorphisms of the prion protein gene (PRNP) play an essential role in the vulnerability of prion diseases. However, to date, investigations of PRNP polymorphisms are rare in cats, which are the major host of feline spongiform encephalopathy (FSE). Thus, we investigated the genetic polymorphisms of the cat PRNP gene and analyzed the structural characteristics of the PrP of cats compared to those of dog, prion disease-resistant animal. To investigate the genetic variations of the cat PRNP gene in 208 cats, we performed amplicon sequencing and examined the genotype, allele and haplotype frequencies of cat PRNP polymorphisms. We evaluated the influence of cat PRNP polymorphisms using PolyPhen-2, PANTHER, PROVEAN and AMYCO. In addition, we carried out structural analysis of cat PrP according to the allele of nonsynonymous single nucleotide polymorphism (SNP) (c.457G > A, Glu153Lys) using Swiss-PdbViewer. Finally, we compared the structural differences between cat and canine PrPs for SNPs associated with prion disease resistance in dogs. We identified a total of 15 polymorphisms, including 14 novel SNPs and one insertion/deletion polymorphism (InDel). Among them, Glu153Lys was predicted to affect the structural stability and amyloid propensity of cat PrP. In addition, asparagine at codon 166 of cat PrP was predicted to have longer hydrogen bond than aspartic acid at codon 163 of canine PrP. Furthermore, substitution to dog-specific amino acids in cat PrP showed an increase in structural stability. To the best of our knowledge, this is the first study regarding the structural characteristics of cat PRNP gene.

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Identification of the novel polymorphisms and potential genetic features of the prion protein gene (PRNP) in horses, a prion disease-resistant animal

Scientific Reports ◽

10.1038/s41598-020-65731-5 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Yong-Chan Kim ◽

Sae-Young Won ◽

Kyoungtag Do ◽

Byung-Hoon Jeong

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Protein Gene ◽

Prion Protein Gene ◽

The Novel ◽

Disease Resistant ◽

Genetic Features ◽

Resistant Animal

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The First Meta-Analysis of the M129V Single-Nucleotide Polymorphism (SNP) of the Prion Protein Gene (PRNP) with Sporadic Creutzfeldt–Jakob Disease

Cells ◽

10.3390/cells10113132 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3132

Author(s):

Yong-Chan Kim ◽

Byung-Hoon Jeong

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Meta Analysis ◽

Prnp Gene ◽

Case Control ◽

Prion Protein Gene ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Jakob Disease ◽

Sporadic Cjd

Prion diseases are fatal, chronic, and incurable neurodegenerative diseases caused by pathogenic forms of prion protein (PrPSc) derived from endogenous forms of prion protein (PrPC). 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.

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Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene ? N. Engl. J. Med. 326, 444–449

Trends in Genetics ◽

10.1016/0168-9525(92)90073-d ◽

1992 ◽

Vol 8 (1) ◽

pp. 123

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Protein Gene ◽

Fatal Familial Insomnia ◽

Prion Protein Gene

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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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Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients

Cells ◽

10.3390/cells9061480 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1480 ◽

Cited By ~ 3

Author(s):

Yong-Chan Kim ◽

Sae-Young Won ◽

Byung-Hoon Jeong

Keyword(s):

Cancer Patient ◽

Cancer Patients ◽

Prion Protein ◽

Patient Population ◽

Somatic Mutations ◽

Protein Gene ◽

Prion Diseases ◽

Prnp Gene ◽

Prion Protein Gene ◽

Total Cancer

Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world; however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.

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