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

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.

First report of a strong association between genetic polymorphisms of the prion protein gene (PRNP) and susceptibility to chronic wasting disease in sika deer (Cervus nippon).

Prion diseases are incurable neurodegenerative disorders caused by proteinase K-resistant prion protein (PrPSc ) derived from normal prion protein (PrPC ) encoded by the prion protein gene (PRNP). Although the cervid PRNP gene plays a pivotal role in the pathological mechanism of chronic wasting disease (CWD), there is no existing association analysis between susceptibility to CWD and genetic polymorphisms of the PRNP gene in sika deer. We investigated genetic polymorphisms of the PRNP gene using amplicon sequencing in sika deer. In addition, to identify a genetic susceptibility factor, we compared the genotype, allele and haplotype frequencies of the PRNP gene between CWD-positive and CWD-negative sika deer. Furthermore, to assess the effect of the genetic polymorphisms on sika deer prion protein (PrP), we performed in silico analysis using PolyPhen-2, PROVEAN and AMYCO. Finally, we analysed the tertiary structure and electrostatic potential of sika deer PrP based on single nucleotide polymorphisms (SNPs) using the SWISS-MODEL and Swiss-PdbViewer programs. We found a total of 24 SNPs of the PRNP gene, including 22 novel SNPs (10 synonymous SNPs and 12 nonsynonymous SNPs), in sika deer. Among the nonsynonymous SNPs, we found a strong association of susceptibility to CWD with c.56G > A (Ser19Asn). In addition, we found that c.56G > A (Ser19Asn), c.296A > T (His99Leu) and c.560T > A (Val187Asp) were predicted to have damaging effects on sika deer PrP. Furthermore, we observed significant alterations in the electrostatic potential of sika deer PrP by genetic polymorphisms of the 187Asp allele. To the best of our knowledge, this was the first association study between genetic polymorphisms of the PRNP gene and susceptibility to CWD in sika deer.

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

Chronic wasting disease (CWD) is a deleterious brain proteinopathy caused by a pathogenic form of prion protein (PrPSc), which is converted from a benign form of prion protein (PrPC) encoded by the prion protein gene (PRNP). In elk, the M132L single nucleotide polymorphism (SNP) of the PRNP gene likely plays a pivotal role in susceptibility to CWD. However, the association of the M132L SNP with susceptibility to CWD has not been evaluated in Korean elk to date. To estimate the association of the M132L SNP with susceptibility to CWD in Korean elk, we investigated the genotype and allele frequencies of the M132L SNP by amplicon sequencing and performed association analysis between CWD-positive and CWD-negative elk. In addition, we performed a meta-analysis to evaluate the association between the M132L SNP and susceptibility to CWD in quantitatively synthesized elk populations. Furthermore, we estimated the effect of the M132L SNP on elk PrP using in silico programs, including PolyPhen-2, PROVEAN, AMYCO and Swiss-PdbViewer. We did not identify a significant association between the M132L SNP of PRNP and susceptibility to CWD in Korean elk. The meta-analysis also did not identify a strong association between the M132L SNP of PRNP and susceptibility to CWD in quantitatively synthesized elk populations. Furthermore, we did not observe significant changes in structure, amyloid propensity or electrostatic potential based on the M132L SNP in elk PrP. To the best of our knowledge, this was the first report of an association analysis and meta-analysis in Korean elk and quantitatively synthesized elk populations, respectively.