|Waldron, Daniel - Texas Agrilife Research|
Submitted to: Gene
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/26/2012
Publication Date: 6/10/2012
Publication URL: http://handle.nal.usda.gov/10113/56584
Citation: White, S.N., Reynolds, J.O., Waldron, D.F., Schneider, D.A., Orourke, K.I. 2012. Extended scrapie incubation time in goats singly heterozygous for PRNP S146 or K222. Gene. 501(1):49-51.
Interpretive Summary: Scrapie eradication in sheep depends in part on strong genetic resistance to classical scrapie. Goats also get scrapie and might transmit it, but to date there has not been sufficient evidence of equivalent genetic resistance in goats to use in eradication programs. However, two promising prion protein variants (amino acid substitutions S146 and K222) have been identified in goats, and we orally challenged goats with only one copy of either S146 or K222 to test if they were scrapie resistant. All controls developed clinical scrapie disease by an average of 24 months, but all S146 and K222 animals remain scrapie negative by both biopsy testing and clinical signs at much longer times since inoculation. Recent reports indicate very small numbers of goats with a single copy of S146 or K222 have become naturally infected with scrapie, suggesting a single copy is not enough to achieve complete resistance but rather may extend the time from infection to disease. The oral challenge results presented here confirm extended time from infection to disease for K222 from a very recent direct into-the-brain inoculation study, and provide the first demonstration of extended incubation time for S146 animals. These results suggest eradication programs might include longer trace-back histories for K222 and S146 animals since disease may take so long to develop. The results also suggest additional studies in animals with two copies of K222 or S146 to assess potential scrapie resistance.
Technical Abstract: Scrapie is the transmissible spongiform encephalopathy (TSE) of sheep and goats, and scrapie eradication in sheep is based in part on strong genetic resistance to classical scrapie. Goats may serve as a scrapie reservoir, and to date there has been no experimental inoculation confirming strong genetic resistance in goats.Two prion protein variants (amino acid substitutions S146 and K222) in goats have been significantly underrepresented in scrapie cases though present in scrapie-exposed flocks, and have demonstrated low cellfree protein conversion efficiency to the disease form (PrPD). To test degree of genetic resistance conferred in live animals with consistent exposure, we performed the first oral scrapie challenge of goats singly heterozygous for either PRNP S146 or K222. All N146-Q222 homozygotes became clinically scrapie positive by an average of 24 months, but all S146 and K222 heterozygotes remain scrapie negative by both rectal biopsy and clinical signs at significantly longer incubation times (P<0.0001 for both comparisons). Recent reports indicate small numbers of S146 and K222 heterozygous goats have become naturally infected with scrapie, suggesting these alleles do not confer complete resistance in the heterozygous state but rather extend incubation. The oral challenge results presented here confirm extended incubation observed in a recent intracerebral challenge of K222 heterozygotes, and to our knowledge provide the first demonstration of extended incubation in S146 heterozygotes. These results suggest longer relevant trace-back histories in scrapie-eradication programs for animals bearing these alleles and strengthen the case for additional challenge experiments in both homozygotes to assess potential scrapie resistance.