Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene

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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The First Report of Polymorphisms and Genetic Features of the prion-like Protein Gene (PRND) in a Prion Disease-Resistant Animal, Dog

International Journal of Molecular Sciences ◽

10.3390/ijms20061404 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1404 ◽

Cited By ~ 14

Author(s):

Sae-Young Won ◽

Yong-Chan Kim ◽

Kiwon Kim ◽

An-Dang Kim ◽

Byung-Hoon Jeong

Keyword(s):

Linkage Disequilibrium ◽

Prion Disease ◽

Genetic Linkage ◽

Protein Gene ◽

Prnp Gene ◽

Nucleotide Polymorphisms ◽

Direct Dna Sequencing ◽

Disease Resistant ◽

Genetic Features ◽

Resistant Animal

Prion disease has displayed large infection host ranges among several species; however, dogs have not been reported to be infected and are considered prion disease-resistant animals. Case-controlled studies in several species, including humans and cattle, indicated a potent association of prion protein gene (PRNP) polymorphisms in the progression of prion disease. Thus, because of the proximal location and similar structure of the PRNP gene among the prion gene family, the prion-like protein gene (PRND) was noted as a novel candidate gene that contributes to prion disease susceptibility. Several case-controlled studies have confirmed the relationship of the PRND gene with prion disease vulnerability, and strong genetic linkage disequilibrium blocks were identified in prion-susceptible species between the PRNP and PRND genes. However, to date, polymorphisms of the dog PRND gene have not been reported, and the genetic linkage between the PRNP and PRND genes has not been examined thus far. Here, we first investigated dog PRND polymorphisms in 207 dog DNA samples using direct DNA sequencing. A total of four novel single nucleotide polymorphisms (SNPs), including one nonsynonymous SNP (c.149G>A, R50H), were identified in this study. We also found two major haplotypes among the four novel SNPs. In addition, we compared the genotype and allele frequencies of the c.149G>A (R50H) SNP and found significantly different distributions among eight dog breeds. Furthermore, we annotated the c.149G>A (R50H) SNP of the dog PRND gene using in silico tools, PolyPhen-2, PROVEAN, and PANTHER. Finally, we examined linkage disequilibrium between the PRNP and PRND genes in dogs. Interestingly, we did not find a strong genetic linkage between these two genes. To the best of our knowledge, this was the first genetic study of the PRND gene in a prion disease-resistant animal, a dog.

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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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Phenotypic heterogeneity and genetic modifiers in prion disease caused by a Pro102Leu mutation in the PRNP gene

Nature Clinical Practice Neurology ◽

10.1038/ncpneuro0998 ◽

2008 ◽

Vol 5 (2) ◽

pp. 68-69 ◽

Cited By ~ 3

Author(s):

Manuela Neumann

Keyword(s):

Prion Disease ◽

Prnp Gene ◽

Phenotypic Heterogeneity ◽

Genetic Modifiers

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Genetic prion disease: D178N with 129MV disease modifying polymorphism—a clinical phenotype

BMJ Neurology Open ◽

10.1136/bmjno-2020-000074 ◽

2020 ◽

Vol 2 (2) ◽

pp. e000074

Author(s):

Tracie Huey-Lin Tan ◽

Richard J Stark ◽

John A Waterston ◽

Owen White ◽

Dominic Thyagarajan ◽

...

Keyword(s):

Family History ◽

Prion Disease ◽

Neurological Diseases ◽

Prion Diseases ◽

Prnp Gene ◽

Fatal Familial Insomnia ◽

Gene Testing ◽

Positron Emission ◽

Disease Modifying ◽

D178n Mutation

BackgroundHuman prion diseases are a group of rare neurological diseases with a minority due to genetic mutations in the prion protein (PRNP) gene. The D178N mutation is associated with both Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotype modified by a polymorphism at codon 129 with the methionine/valine (MV) polymorphism associated with atypical presentations leading to diagnostic difficulty.CaseWe present a case of fatal familial insomnia secondary to a PRNP D178N mutation with 129MV disease modifying polymorphism who had no family history, normal MRI, electroencephalography (EEG), cerebrospinal fluid (CSF) and positron emission tomography findings and a negative real-time quaking-induced conversion result.ConclusionPatients with genetic prion disease may have no known family history and normal EEG, MRI brain and CSF findings. PRNP gene testing should be considered for patients with subacute progressive neurological and autonomic dysfunction.

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Childhood Onset in Familial Prion Disease With a Novel Mutation in the PRNP Gene

Archives of Neurology ◽

10.1001/archneur.63.7.1016 ◽

2006 ◽

Vol 63 (7) ◽

pp. 1016 ◽

Cited By ~ 15

Author(s):

Ekaterina Rogaeva ◽

Cindy Zadikoff ◽

Jonathan Ponesse ◽

Gerold Schmitt-Ulms ◽

Toshitaka Kawarai ◽

...

Keyword(s):

Prion Disease ◽

Novel Mutation ◽

Prnp Gene ◽

Childhood Onset

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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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