Prion Protein Gene Variability in Spanish Goats. Inference through Susceptibility to Classical Scrapie Strains and Pathogenic Distribution of Peripheral PrPsc

Abstract

Classical scrapie is a neurological disorder of the central nervous system (CNS) characterized by the accumulation of an abnormal, partially protease resistant prion protein (PrPsc) in the CNS and in some peripheral tissues in domestic small ruminants. Whereas the pathological changes and genetic susceptibility of ovine scrapie are well known, caprine scrapie has been less well studied. We report here a pathological study of 13 scrapie-affected goats diagnosed in Spain during the last 9 years. We used immunohistochemical and biochemical techniques to discriminate between classical and atypical scrapie and bovine spongiform encephalopathy (BSE). All the animals displayed PrPsc distribution patterns and western blot characteristics compatible with classical scrapie. In addition, we determined the complete open reading frame sequence of the PRNP in these scrapie-affected animals. The polymorphisms observed were compared with those of the herd mates (n = 665) and with the frequencies of healthy herds (n = 581) of native Spanish goats (Retinta, Pirenaica and Moncaina) and other worldwide breeds reared in Spain (Saanen, Alpine and crossbreed). In total, sixteen polymorphic sites were identified, including the known amino acid substitutions at codons G37V, G127S, M137I, I142M, H143R, R151H, R154H, R211Q, Q222K, G232W, and P240S, and new polymorphisms at codons G74D, M112T, R139S, L141F and Q215R. In addition, the known 42, 138 and 179 silent mutations were detected, and one new one is reported at codon 122. The genetic differences observed in the population studied have been attributed to breed and most of the novel polymorphic codons show frequencies lower than 5%. This work provides the first basis of polymorphic distribution of PRNP in native and worldwide goat breeds reared in Spain.

Role of the Goat K 222 -PrP C Polymorphic Variant in Prion Infection Resistance

“…Since Q 222 -Tg501 mice and K 222 -Tg516 mice express exactly the same PrP C sequence, except for the Q/K 222 amino acid substitution, and have similar PrP C expression levels, we can assume that the lack of transmission efficiency of classical scrapie is linked to the K 222 amino acid. This conclusion is consistent with the results reported in the accompanying article by Lacroux et al (27) and previous epidemiological studies carried out in different European goat scrapie outbreaks where the K 222 -PrP C variant was detected only in healthy goats (12,15,23,24). Taken together, these results suggest that the K 222 variant of goat PrP C is strongly resistant to a wide range of classical scrapie strains.…”

“…In goats, half a hundred polymorphisms in the open reading frame (ORF) of the prnp gene have been described (10)(11)(12), including some silent mutations, a three-octapeptide-repeat variant (13), and a nonsense mutation at codon 32 (14). Although several polymorphisms are shared by sheep and goats, to date, only some correlations between some variants of goat PrP C (goPrP C ) and susceptibility to TSE have been published.…”

“…However, the most encouraging results are those related to the Q/K 222 polymorphism. The absence or marked underrepresentation of scrapie-positive goats expressing the K 222 variant in numerous herds from different countries (11,12,15,20,(22)(23)(24)(25) suggests that the K 222 -PrP C variant strongly influences goat susceptibility to TSE agents. Recently, heterozygous Q/K 222 goats were reported to show a strong resistance to classical scrapie after intracerebral (i.c.)…”

Review: A review on classical and atypical scrapie in caprine: Prion protein gene polymorphisms and their role in the disease

“…In Mexican goats, allelic variants F/L 201 in linkage with P/S 240 were found, in addition to P/Q 168 , which has also been described in Italian, Greek and Cypriot goats (Goldmann et al, 2011). A recent study identified five new polymorphisms of the PRNP that lead to amino acid changes (G/D 74 , M/T 112 , R/S 139 , L/F 141 and Q/R 215 ) and a new silent mutation at codon 122 in Spanish goats (Acín et al, 2013). Kipanyula et al (2014) described two additional new polymorphisms in Small East African and Norwegian white goats, A/V 116 and Q/L220, respectively.…”

Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells

“…Similarly to sheep, the caprine Prnp gene is highly polymorphic. 6,[9][10][11][12][13][14][15][16] Field studies, conducted in different countries on a variety of goat breeds, assigned some degree of protection against scrapie to the following alleles Met-142, Arg-143, Asp-146, Ser-146, His-154, Gln-211 and Lys-222. 11,13,14,[17][18][19][20][21][22][23] Among these, Met-142 is linked to prolonged incubation period, 13,17,21,23 while Arg-143 18 and His-154 14,18,19,21,23 are associated with moderate protection.…”