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 , mouflon , sheep , 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: unknown

Disease-related: yes

Year key variant first reported: 1996

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, calssical; scrapie, atypical

Species-specific description: A review of classical and atypical scrapie in sheep and goat is provided by Acin et al. (2021). The European Food Safety Authority (EFSA) panel on biological hazards (2017) reviewed information relating to genetic resistance of transmissible spongiform encephalopathies in goats and developed a tool to "evaluate the genetic resistance to classical scrapie of alleles in the goat PRNP gene, which considers both the weight of evidence and strength of resistance for each allele of interest."

Molecular basis: Gelasakis et al. (2021): in goats “more than 50 PRNP gene polymorphisms have been found, however, their role regarding the incubation period and the susceptibility to classical scrapie has not been adequately documented.” Goldmann et al. (1996) reported a goat PRNP variant that is "identical to the most common sheep PrP protein variant (Ala136-Arg154-Gln171). The dimorphism at codon 142 (Ile --> Met) appeared to be associated with differing disease incubation periods in goats experimentally infected with isolates of bovine spongiform encephalopathy, sheep scrapie CH1641 or sheep-passaged ME7 scrapie." Vaccari et al. (2006) reported an "allelic variant encoding lysine at position 222 could be a valuable candidate to select in the framework of appropriate breeding programmes for scrapie resistance in goats." Papasavva-Stylianou et al. (2007) reported "novel amino acid polymorphisms were detected at [codon] 146 (N-->S or D) . . . The two novel polymorphisms at codon 146 were found only in the healthy control and scrapie-negative goats. By comparison, none of the scrapie-affected goats encoded these polymorphisms." Benistad et al. (2012) reported a nonsense variant (now called Ter) in codon 32 of the PRNP gene that results in "Healthy [Norwegian dairy] goats naturally devoid of prion protein". The authors predicted that these goats would be "resistant to prion disease" because they completely lack the prion protein which, when misfolded, is causative of spongiform encephalopathy. In a comprehensive comparison of +/+, +/Ter and Ter/Ter goats, Salvesen et al. (2020) showed "that goats naturally devoid of PrPC do not replicate prions and are therefore resistant to prion disease. The onset of disease and the progression of clinical signs is delayed in heterozygous animals. Pathological changes and the distribution of PrPSc in the CNS were similar in PRNP+/+ and PRNP+/Ter goats, and there was only a limited peripheral spread of PrPSc to head lymph nodes and nervous tissue in close proximity to the CNS." Gelasakis et al. (2021) investigated “brain samples (n = 525) from scrapie-affected (n = 282) and non-affected (n = 243) animals within the national surveillance program, and (ii) individual blood samples (n = 1708) from affected (n = 241) and non-affected (n = 1467) herds, in a large part of mainland Greece and its islands … . A dedicated Taqman method was used to test for amino acid polymorphisms 110T/P, 146N/S/D, 211R/Q, and 222Q/K.” The authors concluded that "breeding programs in Karpathos could focus on codon 146D, while in other regions carriers of the 110P and 222K allele should be sought.” Adeola et al. (2023) "evaluated the genetic and allele distributions of PRNP polymorphism in 132 Nigerian goats and compared them with publicly available studies on scrapie-affected goats. ... Our study revealed 29 SNPs in Nigerian goats, of which 14 were non-synonymous, and 23 were novel. There were significant differences (P < 0.001) in the allele frequencies of PRNP codons 139, 146, 154 and 193 in Nigerian goats compared with scrapie-affected goats, except for Northern Italian goats at codon 154."

Genetic testing: Sacchi et al. (2018): "The European Union has implemented breeding programmes to increase scrapie resistance in sheep. A similar approach can be applied also in goats since the K222 allele provides a level of resistance equivalent to that of ARR in sheep. The European Food Safety Authority stated that breeding for resistance could be offered as an option for Member States to control classical scrapie in goats." EFSA panel on biological hazards (2017) "The K222, D146 and S146 alleles confer genetic resistance to classical scrapie strains known to occur in the EU goat population. The K222 polymorphism confers resistance against a variety of EU classical scrapie isolates that may reflect a variety of scrapie strains. However, there is no assurance that K222 carriers would be resistant to all TSE agent strains currently circulating in the EU goat population. The D146 and S146 alleles are associated with strong resistance against scrapie agent(s) currently circulating in Cyprus. However, data remain insufficient to assess the level of resistance that D146 and S146 might provide against other classical scrapie agents circulating in other EU goat populations. The weight of evidence for K222 is greater than that currently available for the D146 and S146 alleles and for the ARR allele in sheep at the time the 2002 SSC opinion was produced. ... Due to insufficient data, it is not possible to provide a ranking of susceptibility at genotype level. Based on a combination of the ‘weight of evidence’ and the ‘strength of resistance’, alleles can currently be ranked as follows, from high to low classical scrapie resistance: K222 > D146 = S146 >Q211 = H154 = M142 > S127 = H143 > wild type. ... There is extremely limited data on the susceptibility of goats to either atypical scrapie or BSE for the nine alleles of interest. For atypical scrapie, it was hypothesised that the H154 allele is likely to be associated with higher risk of developing atypical scrapie. For BSE, there are currently no data available on the resistance/susceptibility to BSE infection in D146 and S146 allele carriers, but an oral challenge study indicated incomplete resistance to BSE in K222 allele carriers. There are no data available on the susceptibility of goats with the H154 allele to BSE infection."

Associated gene: