Two novel amino acid substitutions in highly conserved regions of prion protein (PrP) and a high frequency of a scrapie protective variant in native Ethiopian goats

Abstract

Background Polymorphisms of the prion protein gene may influence scrapie susceptibility in small ruminants through modified protein conformation. At least 47 amino acid substitutions and 19 silent polymorphisms have been described in goat PRNP reported from several countries. The objective of this study was to investigate PRNP polymorphisms of native Ethiopian goat breeds and compare the results with other goat breeds. Results The analysis of the prion protein gene PRNP in 229 goats belonging to three of the main Ethiopian native goat breeds showed a remarkably high frequency (> 34.6%) of p.(Asn146Ser) in these breeds, a variant involved in scrapie resistance in Cyprus. In addition, two novel amino-acid substitutions p.(Gly127Ala) and p.(Thr193Ile), with frequencies ranging from 1.5 to 7.3% were detected. Both amino acids are well conserved in prion proteins (PrP) of most species and these changes have never been reported before in goats worldwide. Residue 127 is within the N–terminal domain of PrP and is probably involved in the recruitment of neural cell adhesion molecules (NCAM). Residue 193 is within the highly conserved string of 4 threonines that plays a role in determining the efficiency of prion protein conversion towards its pathological form. Conclusion Two novel coding polymorphisms and a high frequency of a scrapie protective variant indicate a high level of genetic diversity in PRNP of Ethiopian goats. This finding increases the interest in exploring PRNP polymorphisms of native goat breeds in areas where cross breeding with foreign goats has rarely occurred. Electronic supplementary material The online version of this article (10.1186/s12917-019-1870-4) contains supplementary material, which is available to authorized users.

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

“…R154H variant in the Algerian breed has been reported in 15-26% of the study population 9 . The variant T193I was first reported in a recent study by Vitale M. et al, 2019 at a frequency similar to the current observation 12 . The overall frequency of serine to proline substitution at 240 positions in the present study was similar to Anatolian goat breeds (0.08) 26 but higher than the other Ethiopian goat as shown in the above table.…”

“…NS146 was reported in 20.4% of healthy Cyproytic goats 27 . R154H variant was detected at a low frequency in Afar(present study), Western highland, Long Eared Somali, and Aegean region goat breeds 12,26 . R154H variant in the Algerian breed has been reported in 15-26% of the study population 9 .…”

“…Substitution like this may disturb the ionic interaction and might cause loss of interaction with other molecule such as GRB2, ERI3 and SYN1 as annotated in UniProt-P52113. Similarily, the study by Vitale et al 2019, associated the importance of novel variants in the normal cellular function of prion protein especially its interaction with neural cell adhesion molecules (NCAM) 12 .…”

“…Unlike many other countries, prion disease surveillances and exclusive prion gene genotyping were never conducted in sub-Saharan countries. So far, only a few studies reported polymorphisms in the PRNP of native East African goat breeds 10,12,23 . In the present study, we considered Ethiopian native goat breeds (Afar and Arsi-Bale) to identify variants and their potential implication in the prion protein dynamics computationally.…”

Five Novel PRNP Gene Polymorphisms and Their Potential Effect on Scrapie Susceptibility in Three Native Ethiopian Sheep Breeds

“…Amino acids at codon 126 and 127 are localized in the highly conserved glycine rich motif GAVVG 126 G 127 LGGYMLG.This residue was reported to antagonize prion disease development by blocking amyloidal fibril formation [2]. A recent work by Vitale et al,2019 reported polymorphism at this position and implicated its importance in the normal cellular function of prion protein [21].The sequence variation in palindrome residue (PrP 113-120 ) and glycine repeat regions (PrP 124-128 ) synergistically may affect cellular prion protein conformational flexibility.…”