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

Eden Yitna Teferedegn,Yalçın Yaman,Cemal Ün

doi:10.1038/s41598-020-63874-z

Eden Yitna Teferedegn, Yalçın Yaman + Show 1 more

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https://doi.org/10.1038/s41598-020-63874-z

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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.

Highlights

Prion diseases are lethal neurodegenerative disease of humans and animals caused by the misfolding of prion protein[1]
We considered Ethiopian native goat breeds (Afar and Arsi-Bale) to identify variants and their potential implication in the prion protein dynamics computationally
The resistant allele N146S was found at a frequency of 0.54 in Arsi-Bale and 0.60 in Afar breeds

Summary

Introduction

Prion diseases are lethal neurodegenerative disease of humans and animals caused by the misfolding of prion protein[1]. R139S in Algeria[9], A116V in Tanzania[10], G134E and Q163P in Turkey[11] and G127A and T193I in Ethiopia[12] were novel (at the time of the report) substitutions discovered in the respective area of study. Alleles such as M142, D145, S146, H154, Q211, and K222 were experimentally found to either extend scrapie incubation period or increase resistance[8,13,14,15,16]. We considered Ethiopian native goat breeds (Afar and Arsi-Bale) to identify variants and their potential implication in the prion protein dynamics computationally. Data from experimental and computational pipelines (MINNUS, SDM, and MILAMP data servers) was triangulated to increase the power of the tests used

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