In other species: Mallard , chicken , Ring-necked pheasant , white-tufted-ear marmoset , macaques , crab-eating macaque , Rhesus monkey , dog , domestic ferret , domestic cat , puma , horse , pig , Arabian camel , deer , Eurasian elk , Western roe deer , red deer , Eastern wapiti , sika deer , Manchurian Wapiti , reindeer , black-tailed deer , white-tailed deer , American bison , taurine cattle , goat , mouflon , eland , greater kudu , gemsbok , rabbit , golden hamster , domestic guinea pig , domestic yak , chital , fallow deer , cheetah , raccoon dog , bighorn sheep , blue antelope , Arabian oryx , scimitar-horned oryx , nyala , Spanish ibex , water buffalo , Japanese quail , Pyrenean chamois , Iberian red deer , Bank vole , American mink

Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 176640 (gene) , 245300 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0006825: kuru

Mendelian trait/disorder: no

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1990

Cross-species summary: Spongiform encephalopathies are a class of fatal neurological diseases. Clinical signs are characteristic of a progressive degeneration of the central nervous system; they include pruritis, abnormalities of gait and recumbency. Death is inevitable. On post-mortem, brain histopathology shows a characteristic spongy appearance. The infectious agent is a modified form of a protein encoded by a gene in the host. The name given to this infectious particle is prion. The host gene is called the prion protein (PrP) gene, which is a normal part of the genome of mammals and chickens. Its polypeptide product, called cellular PrP(superscript C), is a naturally-occurring protein attached to the outer surface of neurones and some other cells. PrP(superscript C) appears to play a role in maintaining the Purkinje cells of the cerebellum, which are essential for balance and muscular function. The infectious agent, called scrapie PrP(superscript Sc), is a modifed form of PrP(superscript C), where the modifications involve glycosylation and the creation of intra-strand di-sulphide bonds. It is important to realise that these modifications involve no change in amino acid sequence. When PrP(superscript Sc) molecules enter a previously uninfected host, they convert the naturally occurring PrP(superscript C) molecules, produced by the host gene, into infectious PrP(superscript Sc) particles, which ultimately cause clinical signs in that animal, and which can spread to other animals, both horizontally (by infection) and vertically (by maternal transmission). In ruminants the disease has been called bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats and chronic wasting disease (CWD) in cervids.

Species-specific name: Scrapie, classical; scrapie, atypical

Species-specific description: This disease has been recognised in sheep for many centuries. The name arises from the common practice of affected sheep rubbing (scraping) against fence posts. In sheep, the PrP gene is about 20 kb long, consisting of three exons encoding a peptide comprising approximately 250 amino acids. Extensive polymorphism has been discovered in codons 136, 154 and 171, giving rise to amino-acid substitutions at these sites. There is substantial evidence that at least some of this polymorphism is strongly associated with susceptibility/resistance to scrapie. The most likely explanation for this association is that some amino-acid sequences are able to form themselves into the infectious agent, PrP(superscript Sc), without the intervention of other PrP(superscript Sc) particles. Although having been studied for decades, scrapie has been the centre of intense scientific and political attention since 1988, when bovine spongiform encephalopathy (BSE or mad cow disease) was recognised as a new disease, apparently having arisen from the practice of feeding insufficiently-heated sheep offal to cattle. On the strength of the associations mentioned above, The National Scrapie Plan for Britain commenced in January 2002 (Arnold et al., 2002). This is a large program that involves genotyping breeding stock for the three polymorphims within the PrP gene, and issuing certificates on the basis of the genotyping. Similar schemes are underway in France and the Netherlands [FN 13 Jan 2003]. A recent review of classical and atypical scrapie in sheep and goat is provided by Acin et al. (2021)

Inheritance: Parry (1960, 1962) provided substantial evidence of autosomal recessive inheritance of susceptibility to naturally-occurring scrapie. Dickinson and Outram (1988) and Foster and Dickinson (1988) reported the same type of single-gene inheritance for incubation time in experimentally-infected sheep, and named the gene Sip (Scrapie incubation time), with two alleles sA (short incubation, i.e. susceptible) and pA (long incubation).

Markers: Hunter et al. (1989) reported linkage between the Sip gene and the PrP gene encoding prion protein. Goldman et al. (1991) provided supporting evidence. Goldmann et al. (1990) cloned and sequenced the sheep PrP gene, identified the p.R171Q variant, and provided evidence that it "may be related to the alleles of the scrapie incubation-control gene in this species". Laplanche et al. (1993) identified variants p.A136V and p.R154H, reporting the former being strongly associated with susceptibility. The p.171 results were confirmed and extended by Goldmann et al. (1994) and O'Rourke et al. (1994). Westaway et al. (1994) also cloned and sequenced the sheep PrP gene, and provided strong evidence that homozygosity for the 171Q variant "is necessary but not sufficient for the development of natural scrapie". Cassmann et al. (2019) reported that a different 171 allele, namely 171K (lysine), confers greater resistance than the 171Q allele: "sheep with the KK171 genotype are resistant to scrapie via oronasal exposure and . . . sheep with the QK171 genotype have prolonged incubation relative to QQ171 sheep". Teferedegn et al. (2020) reported several new variants in Ethiopian sheep breeds. Rashaydeh et al. (2023) reported twenty-seven amino acid substitutions in PRNP in Awassi sheep. "Eight of them (R40Q, G65E, H88L, S98T, A118P, S138T, V192F and L250I) have not been previously reported."

Associated gene: