Association Study of the M132L Single Nucleotide Polymorphism With Susceptibility to Chronic Wasting Disease in Korean Elk: A Meta-Analysis

Jeong

2022

Front. Vet. Sci.

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Prion diseases are irreversible neurodegenerative disorders caused by the aggregated form of prion protein (PrPSc) derived from the normal form of prion protein (PrPC). Previous studies have reported that shadow of prion protein (Sho) interacts with prion protein (PrP) and accelerates the conversion of PrPC to PrPSc. In addition, genetic polymorphisms of the shadow of the prion protein gene (SPRN) are related to the vulnerability of prion diseases in various hosts. However, to date, polymorphisms and genetic features of the SPRN gene have not been investigated in chickens, which are prion disease-resistant animals. We investigated genetic polymorphisms of the SPRN gene in 2 breeds of chickens, i.e., Dekalb White and Ross, using amplicon sequencing. We analyzed genotype, allele and haplotype frequencies and linkage disequilibrium (LD) among the genetic polymorphisms. In addition, we compared the amino acid sequences of Sho among several prion-related species to identify the unique genetic features of chicken Sho using ClustalW. Furthermore, we evaluated the N-terminal signal peptide and glycosylphosphatidylinositol (GPI)-anchor using SignalP and PredGPI, respectively. Finally, we compared the number of SPRN polymorphisms between prion disease-resistant and prion disease-susceptible animals. We identified 7 novel single nucleotide polymorphisms (SNPs), including 1 synonymous SNP in the open reading frame (ORF) of the chicken SPRN gene. We also found significantly different genotypes, allele frequencies and haplotypes between the 2 chicken breeds. In addition, we found that the interaction regions between Sho and PrP and the NXT glycosylation motif were conserved among all species. Notably, sequence similarity was extremely low in the N-terminal and C-terminal regions between mammals and chickens. Furthermore, we found that chicken Sho was the longest N-terminal signal peptide, and the amino acids of the cutting site of chicken are different from those of mammals. Last, unlike other species investigated, omega-site and signal sequences of the GPI-anchor were not found in chickens. To the best of our knowledge, this is the first report of genetic polymorphisms of the SPRN gene in chickens.

Section: Introductionmentioning

confidence: 99%

The First Report of Polymorphisms and Genetic Characteristics of the Shadow of Prion Protein (SPRN) in Prion Disease-Resistant Animal, Chickens

Jeong

2022

Front. Vet. Sci.

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“…However, since these in silico analyses were the prediction, further validation of the N-terminal signal sequence and omega site of GPI-anchor is highly desirable using biochemical analyses. In recent studies, the Sho protein has been shown to have a stress-resistant function and to be essential for early mouse embryogenesis and mammary development and differentiation [ 6 , 7 , 29 ]. Future analysis of the effect of GPI-anchor-related differences on the native function and physiology of the Sho protein is greatly desired.…”

Section: Discussionmentioning

confidence: 99%

“…Prion diseases are fatal and irreversible neurodegenerative disorders caused by a pathogenic isoform of prion protein (PrP Sc ) changed from normal prion protein (PrP C ) and have been reported in various hosts, including Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI) and Gerstmann–Sträussler–Scheinker syndrome (GSS) in humans; scrapie in sheep and goats; bovine spongiform encephalopathy (BSE) in cattle; transmissible mink encephalopathy (TME) in mink; chronic wasting disease in elk and deer; and feline spongiform encephalopathy (FSE) in cats, cheetahs and pumas [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Prion diseases are classified into three major types according to etiology, including sporadic, iatrogenic and genetic forms [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Polymorphisms and Genetic Characteristics of the Shadow of Prion Protein Gene (SPRN) in Cats, Hosts of Feline Spongiform Encephalopathy

Kim³

et al. 2022

Viruses

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Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by pathogenic prion protein (PrPSc) originating from normal prion protein (PrPC) 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.

“…White et al also found that the 132L allele was less observed among CWD cases in 559 captive and free-ranging elk from a different geographic region in the USA [ 13 ]. However, other studies did not find that the genotype and allele frequencies of the M132L single nucleotide polymorphism (SNP) were associated with susceptibility to CWD in the USA and Korea [ 14 , 15 ]. In addition, a meta-analysis of the three previous studies also did not identify a relationship between the M132L SNP and susceptibility to CWD in all genetic models [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, other studies did not find that the genotype and allele frequencies of the M132L single nucleotide polymorphism (SNP) were associated with susceptibility to CWD in the USA and Korea [ 14 , 15 ]. In addition, a meta-analysis of the three previous studies also did not identify a relationship between the M132L SNP and susceptibility to CWD in all genetic models [ 15 ]. Furthermore, real-time quaking-induced conversion (RT-QuIC) shows that the conversion efficiency of PrP Sc of a specific genotype was not high but that the conversion efficiency of PrP Sc was high when the genotype of the codon was identical between the template and seed [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel risk factor for chronic wasting disease (CWD) in elk: S100G single nucleotide polymorphism (SNP) of the prion protein gene (PRNP)

Lee

Won

et al. 2023

Vet Res

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Prion diseases are fatal and malignant infectious encephalopathies induced by the pathogenic form of prion protein (PrPSc) originating from benign prion protein (PrPC). A previous study reported that the M132L single nucleotide polymorphism (SNP) of the prion protein gene (PRNP) is associated with susceptibility to chronic wasting disease (CWD) in elk. However, a recent meta-analysis integrated previous studies that did not find an association between the M132L SNP and susceptibility to CWD. Thus, there is controversy about the effect of M132L SNP on susceptibility to CWD. In the present study, we investigated novel risk factors for CWD in elk. We investigated genetic polymorphisms of the PRNP gene by amplicon sequencing and compared genotype, allele, and haplotype frequencies between CWD-positive and CWD-negative elk. In addition, we performed a linkage disequilibrium (LD) analysis by the Haploview version 4.2 program. Furthermore, we evaluated the 3D structure and electrostatic potential of elk prion protein (PrP) according to the S100G SNP using AlphaFold and the Swiss-PdbViewer 4.1 program. Finally, we analyzed the free energy change of elk PrP according to the S100G SNP using I-mutant 3.0 and CUPSAT. We identified 23 novel SNP of the elk PRNP gene in 248 elk. We found a strong association between PRNP SNP and susceptibility to CWD in elk. Among those SNP, S100G is the only non-synonymous SNP. We identified that S100G is predicted to change the electrostatic potential and free energy of elk PrP. To the best of our knowledge, this was the first report of a novel risk factor, the S100G SNP, for CWD.