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

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1480 ◽  
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.

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

2020 ◽  
Vol 21 (12) ◽  
pp. 4246 ◽  
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.

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

Genes ◽  
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.

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

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 193
Author(s):  
Min-Ju Jeong ◽  
Yong-Chan Kim ◽  
Byung-Hoon Jeong
Keyword(s):  
Prion Protein ◽  
Dna Sequence ◽  
Prion Disease ◽  
Protein Gene ◽  
Prnp Gene ◽  
Pekin Duck ◽  
Prion Protein Gene ◽  
First Report ◽  
Aggregation Propensity ◽  
Pekin 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.

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

Cells ◽  
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.

scholarly journals No polymorphisms in the coding region of the prion-like protein gene in Thoroughbred racehorses

2019 ◽  
Vol 67 (2) ◽  
pp. 174-182 ◽  
Author(s):  
Min-Ju Jeong ◽  
Byung-Hoon Jeong
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Protein Gene ◽  
Prion Diseases ◽  
Amino Acid Sequences ◽  
Prion Protein Gene ◽  
Coding Region ◽  
Thoroughbred Racehorses ◽  
Thoroughbred Horses ◽  
Protein Isoform

Prion diseases are fatal neurodegenerative diseases characterised by the accumulation of an abnormal prion protein isoform (PrPSc), which is converted from the normal prion protein (PrPC). Prion diseases have been reported in an extensive number of species but not in horses up to now; therefore, horses are known to be a species resistant to prion diseases. The prion-like protein gene (PRND) is closely located downstream of the prion protein gene (PRNP) and the prion-like protein (Doppel) is a homologue with PrP. Previous studies have shown that an association between prion diseases and polymorphisms of the PRND gene is reported in the main hosts of prion diseases. Hence, we examined the genetic variations of the PRND gene in Thoroughbred horses. Interestingly, polymorphisms of the PRND gene were not detected. In addition, we conducted a comparative analysis of the amino acid sequences of the PRND gene to identify the differences between horses and other species. The amino acid sequence of the horse PRND gene showed the highest identity to that of sheep (83.7%), followed by that of goats, cattle and humans. To the best of our knowledge, this is the first genetic study of the PRND gene in horses.

Prion Diseases

2017 ◽  
Author(s):  
James A. Mastrianni ◽  
Joshuae G. Gallardo
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Protein Gene ◽  
Prion Diseases ◽  
Prion Protein Gene ◽  
Secondary Transmission ◽  
Jakob Disease

Prion diseases are transmissible fatal neurodegenerative disorders resulting from the accumulation of misfolded prion protein. Although primarily sporadic diseases, 5% to 10% result from a mutation of the prion protein gene (PRNP), and less than 1% occur from exposure to prions. The current family of prion diseases includes Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal insomnia (FI), variant CJD (vCJD), and variably protease-sensitive prionopathy (VPSPr). Kuru is a disease of historical interest that was transmitted through cannibalistic rituals. Iatrogenic CJD (iCJD) is the result of secondary transmission of prion disease from contaminated biologicals.

Polymorphism of the prion protein gene (PRNP) in Polish Merino and Suffolk sheep flocks

2016 ◽  
Vol 16 (2) ◽  
pp. 9-21
Author(s):  
Roman Niżnikowski ◽  
Marcin Świątek ◽  
Żaneta Szymańska ◽  
Magdalena Ślęzak ◽  
Krzysztof Głowacz
Keyword(s):  
Gene Polymorphism ◽  
Prion Protein ◽  
Protein Gene ◽  
Prnp Gene ◽  
Prion Protein Gene ◽  
Merino Sheep ◽  
One Year ◽  
Very High ◽  
Suffolk Sheep

The aim of the study was to investigate the distribution of prion protein PRNP alleles in flocks of Polish Merino and Suffolk sheep. The research was conducted in 2012-2017 on ewes and rams kept in the Golina Wielka sheepfold (Greater Poland Voivodeship, Poland). All animals (264 ♀ and 64 ♂ Polish Merino; 98 ♀ and 73 ♂ Suffolk) were up to one year old. PRNP gene polymorphism was identified in the sheep. The frequency of scrapie alleles and genotypes was found to be highly significantly influenced by the breed and significantly influenced by the year in the case of Polish Merino sheep. Five alleles (ALRR, ALRQ, ALHQ, AFRQ and VLRQ) were detected in Polish Merino sheep, leading to the identification of 10 PRNP genotypes. In the Suffolk breed, three alleles (ALRR, ALRQ and ALHQ) and three genotypes were identified. In the Polish Merino breed, the frequency of the ALRR/ALRQ genotype was high and was the highest among all genotypes, followed by ALRR/ALRR. The level of genotypes containing valine at codon 136 was very low. In the Suffolk breed, the frequency of the ALRR/ALRR genotype was very high, and there were no alleles with valine at codon 136. In addition, in Polish Merino sheep, phenylalanine at codon 141 was detected only in the AFRQ allele, which appeared in two genotypes (in combination with ALRR and ALRQ).

scholarly journals The first report of prion-related protein gene (PRNT) polymorphisms in goat

2017 ◽  
Vol 65 (2) ◽  
pp. 291-300 ◽  
Author(s):  
Yong-Chan Kim ◽  
Byung-Hoon Jeong
Keyword(s):  
Gene Family ◽  
Prion Protein ◽  
Dna Sequences ◽  
Protein Gene ◽  
Prion Diseases ◽  
Genetic Research ◽  
Comparative Sequence Analysis ◽  
Prion Protein Gene ◽  
Related Protein ◽  
Prion Gene

Prion protein is encoded by the prion protein gene (PRNP). Polymorphisms of several members of the prion gene family have shown association with prion diseases in several species. Recent studies on a novel member of the prion gene family in rams have shown that prion-related protein gene (PRNT) has a linkage with codon 26 of prion-like protein (PRND). In a previous study, codon 26 polymorphism of PRND has shown connection with PRNP haplotype which is strongly associated with scrapie vulnerability. In addition, the genotype of a single nucleotide polymorphism (SNP) at codon 26 of PRND is related to fertilisation capacity. These findings necessitate studies on the SNP of PRNT gene which is connected with PRND. In goat, several polymorphism studies have been performed for PRNP, PRND, and shadow of prion protein gene (SPRN). However, polymorphism on PRNT has not been reported. Hence, the objective of this study was to determine the genotype and allelic distribution of SNPs of PRNT in 238 Korean native goats and compare PRNT DNA sequences between Korean native goats and several ruminant species. A total of five SNPs, including PRNT c.-114G > T, PRNT c.-58A > G in the upstream of PRNT gene, PRNT c.71C > T (p.Ala24Val) and PRNT c.102G > A in the open reading frame (ORF) and c.321C > T in the downstream of PRNT gene, were found in this study. All five SNPs of caprine PRNT gene in Korean native goat are in complete linkage disequilibrium (LD) with a D’ value of 1.0. Interestingly, comparative sequence analysis of the PRNT gene revealed five mismatches between DNA sequences of Korean native goats and those of goats deposited in the GenBank. Korean native black goats also showed 5 mismatches in PRNT ORF with cattle. To the best of our knowledge, this is the first genetic research of the PRNT gene in goat.

CHARACTERISTICS OF ALLELE POOL OF THE ROMANOV SHEEP BREED FOR THE PRION PROTEIN GENE ASSOCIATED WITH GENETIC SUSTAINABILITY TO SCRAPIE

2017 ◽  
Vol 52 (6) ◽  
pp. 1157-1165
Author(s):  
E.A. Gladyr ◽  
◽  
T.E. Deniskova ◽  
V.A. Bagirov ◽  
O.V. Kostyunina ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Gene ◽  
Sheep Breed ◽  
Prion Protein Gene ◽  
Allele Pool
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