Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Abstract

Scrapie is a lethal neurodegenerative disease of sheep and goats caused by the misfolding of the prion protein. Variants such as M142, D145, S146, H154, Q211, and K222 were experimentally found to increase resistance or extend scrapie incubation period in goats. We aimed to identify polymorphisms in the Afar and Arsi-Bale goat breeds of Ethiopia and computationally assess the effect of variants on prion protein stability. In the present study, four non-synonymous novel polymorphisms G67S, W68R, G69D, and R159H in the first octapeptide repeat and the highly conserved C-terminus globular domain of goat PrP were detected. The resistant genotype, S146, was detected in >50% of the present population. The current study population showed a genetic diversity in Ethiopian goat breeds. In the insilico analysis, the R68 variant was predicted to increase stability while S67, D69, and H159 decrease the stability of prion protein. The new variants in the octapeptide repeat motif were predicted to decrease amyloidogenicity but H159 increased the hotspot sequence amyloidogenic propensity. These novel variants could be the source of conformational flexibility that may trigger the gain or loss of function by prion protein. Further experimental study is required to depict the actual effects of variants on prion protein stability.

Figure 1

Novel polymorphism in Afar and Arsi-Bale breeds. (a) functional domain of prion protein; (b) wild type G67, W68 and G69; (c) novel variant S67, R68 and D69; (d) wild type R159; (e) novel variant H159.

Figure 2

Relative solvent accessibility of Afar and Arsi-Bale goat breeds prion protein with wild type and new varint. Relative solvent accessibility of the:- (a) wildtype and (b) the new varinat was indicted in a zoomed in pannel. A scale of 0–9 as a measure of surface exposure to solvent at the right lower corner of the pannel. RSA is the net change at the mutated position in the side chain surface accessible area. Lower red blocks indicate confidence level.

Figure 3

Predicted 3D structure of Afar and Arsi-Bale goat breeds prion protein -UniProt- P52113. (a) wild type: G67 green, W68 blue, G69 magenta and R159 red; (b) 3DWild type:- C-score = −3.24, Estimated TM-score = 0.35 ± 0.12, Estimated RMSD = 13.6 ± 4.0 Å; (c) variant containing structure: S67 green, R68 blue, D69 magenta and HR159 red; (d) 3D mutant structure:-C-score = −3.20, Estimated TM-score = 0.36 ± 0.12, Estimated RMSD = 13.5 ± 4.0 Å.