Abstract
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.
Highlights
Prion diseases, neurodegenerative disorders in humans and animals, are known as transmissible spongiform encephalopathies (TSEs) characterized by a structural folding change from a normal prion protein (PrPC) to a toxic form of prion protein (PrPSc) causing brain lesions [1,2,3]
According to case-controlled studies comparing the genetic distribution of PRND gene polymorphisms in codons 26, 56, 132 and 174 and 3’ untranslated region (UTR) +28, these polymorphisms were involved in the susceptibility to scrapie, bovine spongiform encephalopathy (BSE) and sporadic Creutzfeldt-Jakob disease (CJD) in ruminants and humans [36,37,38,39,40]
The dog PRND gene is composed of two exons
Summary
Neurodegenerative disorders in humans and animals, are known as transmissible spongiform encephalopathies (TSEs) characterized by a structural folding change from a normal prion protein (PrPC) to a toxic form of prion protein (PrPSc) causing brain lesions [1,2,3]. There was no significant difference in the expression level of prion protein in the brain between dogs and other animals [19] Another factor is the genetic characteristic of the prion protein. According to case-controlled studies comparing the genetic distribution of PRND gene polymorphisms in codons 26, 56, 132 and 174 and 3’ untranslated region (UTR) +28, these polymorphisms were involved in the susceptibility to scrapie, BSE and sporadic CJD in ruminants and humans [36,37,38,39,40]. The investigation of the genetic characteristics of the PRND gene in dogs as a prion disease-resistant species will be a very important baseline study to obtain clues on the progression of prion disease
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